CZ281937B6 - Substituted biphenyl pyridones, process of their preparation, pharmaceutical composition containing such compounds and their use - Google Patents

Abstract

Substituted biphenylpyridones of the formula I. The compounds are prepared by alkylating pyridones at the nitrogen atom. Substituted biphenylpyridones are useful as active ingredients in drugs, especially blood pressure lowering and antiatherosclerotic drugs.

Description

Substituted biphenylpyridones, processes for their preparation, pharmaceutical compositions containing them and their use

Technical field

The invention relates to substituted biphenylpyridones, to a process for their preparation and to their use in medicaments, in particular as blood pressure lowering agents and antisclerotic agents.

BACKGROUND OF THE INVENTION

It is known to renin. a proteolytic enzyme, cleaves in vivo from angiotensinogen the decapeptide angiotensin I. which, again in the lungs, kidneys or other tissues, breaks down to the octapeptide angiotensin II. increasing blood pressure. Various effects of angiotensin II, such as vasoconstriction, Na 'retention in the kidneys, aldosterone release in the adrenal glands, and an increase in sympathetic nervous system tone, act synergistically in the sense of elevated blood pressure. In addition, angiotensin II has the property of promoting the growth and multiplication of cells, such as cardiac muscle cells and smooth muscle cells, which, in various disease states (e.g., hypertonia, atherosclerosis and cardiac insufficiency), grow and proliferate more.

A possible intervention in the renin-angiotensin system (RAS) is, in addition to inhibiting renin activity, inhibiting angiotensin-converting enzyme (ACE) activity as well as blocking angiotensin II receptors.

In addition, pyrimidones substituted with biphenyls are known from EP 407 342, EP 424 317, EP 435 827 and EP 419 048.

SUMMARY OF THE INVENTION

The present invention provides substituted biphenylpyridones of formula (I)

(I) in which

R ^l represents straight-chain or branched alkyl having up to 10 carbon .atomy, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms,

- 1 GB 281937 B6

A represents a direct bond, an oxygen atom or a sulfur atom, or a group -CH ₂ - or a group of the formula -NR ⁶ _r wherein:

R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, or

R ⁶ together with R ¹ and the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycle,

R ² . R ^J and R ⁴ are identical or different and represent hydrogen, nitro, cyano, formylovouskupinu or halogen atom, or a linear or branched alkyl, alkenyl. alkynyl, alkoxy or alkylthio having in each case up to 8 carbon atoms, which are optionally up to twice, equally or differently, substituted by hydroxy. cyano. a halogen atom, a carboxyl group, a straight or branched alkoxy, acyl or alkoxycarbonyl group each having up to 6 carbon atoms, or a benzyl, phenyl, phenoxy or benzoyl group, or a 5- to 7-membered, saturated or unsaturated heterocycle of up to 3 heteroatoms; , sulfur and nitrogen, wherein the cycles themselves may be up to twice the same or differently substituted with trifluoromethyl, trifluoromethoxy, halogen, nitro. cyano, hydroxy, hydroxymethyl, or straight or branched alkyl or alkoxy of up to 6 carbon atoms, or straight or branched acyl or alkoxycarbonyl of up to 8 carbon atoms, phenoxycarbonyl, benzyloxycarbonyl or cycloalkoxy, or cycloalkoxy each of from 3 to 8 carbon atoms, a 5- to 7-membered unsaturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen, phenyl, phenoxy or phenylthio, optionally substituted up to three times the same or differently with halogen, nitro, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy or straight or branched alkyl or alkoxy of up to 6 carbon atoms, or tetrazolyl, which is optionally substituted by methyl or a trityl group, or a group of the formula

HC = N-OH, -C = C

CO ₂ R ⁹

-NR ¹⁰ R ¹¹ , -CO-NR ¹⁰ R ^h or -CH ₂ -OR ¹² ,

-2GB 281937 B6 where

R ⁷ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms,

R ⁸ represents a hydrogen atom or a straight or branched alkyl group having up to 8 carbon atoms, which is optionally substituted by a cycloalkyl group having 3 to 6 carbon atoms, a phenyl group or a 5- to 7-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the sulfur group; nitrogen and oxygen, the cyclenes being optionally substituted by hydroxy, hydroxymethyl, halogen or straight or branched alkyl or alkoxy of up to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms,

R ⁷ represents a hydrogen atom, a straight or branched alkyl group having up to 8 carbon atoms or a phenyl group,

R ¹⁰ and R ¹¹ 'are the same or different and represent a hydrogen atom, a C 3 -C 8 cycloalkyl group or a straight or branched alkyl group of up to 8 carbon atoms which is optionally substituted by a phenyl group, and

R ¹² represents a straight or branched acyl group having up to 6 carbon atoms or a benzoyl group, or

-AR ¹ and R ² together denote an alkylene chain of up to 5 carbon atoms,

R ³ represents hydrogen, halogen, cyano, nitroskupřnu, trifluoromethyl, hydroxvskupinu. trifluoromethoxy or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and

D denotes the remainder of the formula

R ¹⁴

R ¹³ in which

R ¹³ is as defined above for R ⁵ and is the same or different with R ⁵ ;

R ¹⁴ denotes a group of the formula -CO-R ¹³ , -CO-NR 6 R ¹⁷ or -SO 2 R ¹⁸ , wherein:

^{R s} represents hydroxyl or straight-chain or branched alkoxy having up to 6 carbon atoms,

-3 CZ 281937 B6

R ¹⁶ and R ¹⁷ are the same or different and have the meanings given above for R ¹⁰ and R ¹¹ , or

R ¹⁶ denotes a hydrogen atom and

R ¹⁷ denotes the group -SO ₂ R ¹⁸ a

R ¹⁸ denotes hydroxyl, straight chain or branched alkoxy or alkyl each having up to 6 carbon atoms, amino or mono- or dialkvlaminoskupinu each having up to 6 carbon atoms or phenyl group which may be optionally substituted up to twice, identically or differently with halogen, trifluoromethyl or a straight or branched alkyl group having up to 4 carbon atoms, or

R ¹⁴ denotes the remainder of the formula

in which

R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, which is optionally substituted by a straight or branched acyl group of up to 6 carbon atoms, or a triphenylmethyl group, and salts thereof.

The substituted biphenylpyridones of the present invention may also exist in the form of their salts. In general, salts with organic or inorganic bases or acids can be mentioned.

Physiologically acceptable salts are preferred within the scope of the present invention. The physiologically acceptable salts of the compounds of the present invention may be salts of said compounds with mineral acids, carboxylic acids or sulfonic acids. Particularly preferred are, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, , fumaric acid, maleic acid or benzoic acid.

Physiologically acceptable salts also include metal or ammonium salts of the compounds of the present invention having a free carboxyl group or a tetrazolyl residue. Particularly preferred are, for example, sodium, potassium, magnesium or calcium salts as well as ammonium salts derived from ammonia or from organic amines, such as, for example, ethylamine, diethylamine, triethylamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylamino-4CZ 281937 B6 ethanol, arginine, lysine, ethylenediamine or 2-phenylethylamine.

The compounds of the present invention may exist in stereoisomeric forms that behave either as an image and a mirror image (enantiomers) or somehow an image and a mirror image 5 (diastereomers). The present invention relates to both enantiomers or diastereomers as well as their respective mixtures. Racemic forms, like diastereomers, can be resolved into known stereoisomers by uniform components (see E. L. Eliel, Stereochemistry of Carbon Compounds, McGraw Hill, 1962).

The heterocycle is generally a 5- to 7-membered, preferably 5- to 6-membered, saturated or unsaturated ring which may contain up to 2 oxygen, sulfur and / or nitrogen atoms as heteroatoms. Five to six-membered rings with one oxygen, sulfur and / or up to two nitrogen atoms are preferred. Preferred are thienyl, furyl, pyrrolyl, pyrazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridysinyl, oxazolyl, thiazolyl, imidazolyl, pyrrolidinyl, piperidinyl, piperazinyl or tetrazolyl.

Particularly preferred are compounds of formula I wherein:

R @ ¹ denotes a straight or branched alkyl group having up to 8 carbon atoms which is optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, hydroxy or straight or branched alkoxy having up to 4 carbon atoms, or cyclopropyl, cyclopentyl, cyclohexyl, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom,

A represents a direct bond, -CH ₂ , oxygen, sulfur or -NH.

R ^2, R ^J, and R ⁴ are identical or different and represent hydrogen, nitro, cyano, formyl, fluorine, chlorine, bromine or iodine, or represents straight-chain or branched alkyl, alkenyl, alkynyl or alkylthio each having up to 6 carbon atoms optionally substituted by hydroxy, cyano, fluorine, chlorine, bromine, carboxyl, straight or branched alkoxy, acyl or alkoxycarbonyl of up to 4 carbon atoms, or benzyl, phenyl, phenoxy, benzoyl or thienyl the cyclenes may themselves be substituted by trifluoromethoxy, trifluoromethyl, hydroxymethyl, fluorine, chlorine, bromine, iodine or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms, or a straight or branched acyl group or alkoxycarbonyl group Up to 6 carbon atoms each, a phenoxycarbonyl group, a benzyloxycarbonyl group or a carboxyl group, or

-5C 281937 B6 cyclopentenyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, furyl, phenyl, phenoxy or phenylthio, optionally substituted up to two times the same or differently with a fluorine atom, a chlorine atom, an iodine atom, a bromine atom, a trifluoromethyl group, a trifluoromethyl group, a trifluoromethyl group, or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms, or a tetrazolyl group optionally substituted by a methyl or trityl group.

or a group of formula -CH = N-OH,

-C =C ^ COR ⁹

-NR ° R, -CO-NR ^io R 'or -CH ₂ -OR ^12, wherein

R ⁷ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms,

R ⁸ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms optionally substituted by cyclopropyl, cyclohexyl, thienyl or phenyl, the cyclenes being optionally substituted by hydroxy, hydroxymethyl or straight or branched alkyl or alkoxy having up to 4 carbon atoms in each case.

R ⁹ represents a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms.

R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a cyclopropyl group, a cyclohexyl group or a straight or branched alkyl group having up to 6 carbon atoms which is optionally substituted by a phenyl group, and

R ¹² represents a straight or branched acyl group having up to 6 carbon atoms, or

-AR ¹ and R ² together denote an alkylene chain of up to 5 carbon atoms,

R ³ represents hydrogen, fluorine, chlorine, bromine, hydroxyl, trifluoromethyl, trifluoromethoxy or straight-chain or branched alkyl or alkoxy each having up to 4 carbon atoms and

-6GB 281937 B6

D denotes the radical of formula r14

R ¹³ in which

R ¹³ is as defined above for R ³ and is the same or different, and

R ^u represents a group ^-CO-R13, -CO-NR ¹⁷ R ^I6, or -SO ₂ R ^18, wherein

R ¹³ denotes a hydroxy group or a straight or branched alkoxy group having up to 4 carbon atoms,

R ¹⁶ and R ¹¹ are the same or different and have the meanings given above for the substituents R ¹⁰ and R.

or

R ¹⁶ denotes a hydrogen atom and

R ¹⁷ denotes the group -SO ₂ R ¹⁸ a

R ^IS denotes a straight or branched alkyl group having up to 4 carbon atoms or a poly group, or

R ¹⁴ represents a radical of the formula

I Ψ I N —ý - N

R ¹⁹ in which

R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, which is optionally substituted by a straight or branched acyl group having up to 4 carbon atoms, or a triphenylmethyl group, and salts thereof.

Particularly preferred are compounds of formula I wherein:

R ¹ represents straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, hydroxy or methoxy, or represents cyclopropyl, chlorine or iodine,

A denotes a direct bond, -CH ₂ - or an oxygen atom,

R ² . R ³ and R ⁴ are the same or different and denote a hydrogen atom, a cyano group, a formyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom or a straight or branched alkyl, alkenyl, alkynyl or alkylthio group of up to 4 carbon atoms; optionally substituted by hydroxy, cyano or straight or branched alkoxy or alkoxycarbonyl having up to 3 carbon atoms, benzyl, phenyl, phenoxy or benzoyl, or straight or branched acyl or alkoxycarbonyl having up to 4 carbon atoms, phenoxy , a benzyloxycarbonyl or carboxyl group, or a cyclopropyl, cyclopentyl, thienyl, phenyl, phenoxy or phenylthio group optionally substituted by a fluorine atom, a chlorine atom, a bromine atom, an iodine atom or a trifluoromethyl group, or a tetrazolyl group, which is optionally substituted by a methyl or trityl group, or a group of the formula -CH = N-OH,

-CO-NR ¹⁰ R ¹¹ or -CH ₂ -OR ¹² ,

-8EN 281937 B6 where

R ⁷ represents a hydrogen atom or a methyl group,

R @ ⁸ denotes a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms which is optionally substituted by a phenyl group which is itself optionally substituted by a hydroxy group, a hydroxymethyl group or a straight or branched alkyl or alkoxy group having up to 3 carbon atoms each;

R ⁹ denotes a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms,

R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a cyclopropyl group, a cyclopentyl group or a straight or branched alkyl group having up to 4 carbon atoms, which is optionally substituted by a phenyl group, and

R ¹² represents a straight or branched acyl group having up to 4 carbon atoms, or

-AR 1 and R ² together denote an alkylene chain of up to 4 carbon atoms,

R ³ represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group;

D denotes the remainder of the formula

R14

R ¹³ in which

R ¹³ denotes a hydrogen atom and

R ¹⁴ represents a group of the formula -CO-R ¹ ', -CO-NR ¹⁶ R ¹⁷ or -SO ₂ -R ¹⁸ , wherein:

R ¹⁵ represents a hydroxy group or a straight or branched alkoxy group having up to 3 carbon atoms,

R ¹⁶ and R ¹⁷ are the same or different and have the meaning given above for the substituents R ¹⁰ and R ¹¹ , or

R ¹⁶ denotes a hydrogen atom and

R ¹⁷ denotes the group -SO ₂ -R ¹⁸ a

-9EN 281937 B6

R ¹⁸ denotes methyl or p-tolyl, or

R ¹⁴ represents a tetrazolyl radical of the formula

in which

R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, which is optionally substituted by a straight or branched acyl group having up to 4 carbon atoms, or a triphenylmethyl group, and salts thereof.

The invention furthermore relates to a process for the preparation of the compounds according to the invention of the formula I, characterized in that the pyridones of the formula II

R ³

(II), wherein R ¹ , R ² , R ⁴ and A are as defined above, are reacted with compounds of formula III

(III) in which:

E represents a halogen atom, preferably bromine and

L represents the remainder of the formula

- 10GB 281937 B6

in which

R ¹³ is as defined above and

R ²⁰ represents an alkoxycarbonyl group having 1 to 4 carbon atoms, or a radical of formula

N - N in inert solvents, in the presence of a base and optionally with the addition of a catalyst, and then, in the case of the tetrazole radical, the triphenylmethyl group is cleaved by means of acids in organic solvents and / or water under conventional conditions and optionally the carbonyl radicals mentioned under R ¹⁴ and / or R ²⁰ , after saponification of 30 corresponding esters by amidation or sulfoamidation by conventional means, and optionally also the substituents R ² , R ³ , R ⁴ , R ³ , R ¹³ and R ^{19 are} varied by known methods.

The process of the present invention can be illustrated, for example, by the following scheme

N - N

- 11 GB 281937 B6

Dimethoxyethane (DME)

DMF. ------------- ► Potassium tert-butylate

CSjCOj

CH ₃ OH

Acetone ·

------ ►

HCl

Suitable solvents for this process are conventional organic solvents which do not change under the reaction conditions. These preferably include ethers such as diethyl ether, dioxane, tetrahydrofuran, glycol dimethyl ether, further hydrocarbons such as benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions, halogenated hydrocarbons such as dichloromethane, trichloromethane, carbon tetrachloride, dichlorethylene, trichlorethylene or chlorobenzene; and ethyl acetate, triethylamine, pyridine, dimethylsulfoxide, dimethylformamide, dimethoxyethane, hexamethylphosphoric triamide, acetonitrile, acetone or nitromethane. It is also possible to use mixtures of the solvents mentioned. Tetrahydrofuran, acetone, dimethylformamide or dimethoxyethane are preferred.

In general, inorganic or organic bases can be used as bases for the process according to the invention. These preferably include alkali metal hydroxides such as sodium hydroxide or potassium hydroxide, alkaline earth metal hydroxides such as barium hydroxide. alkali metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate or cesium carbonate, alkali metal or alkaline earth metal alcoholates or amides such as sodium ethoxide, potassium ethoxide, sodium methoxide, methoxide potassium, tert-butylate or lithium diisopropylamide (LDA), organic amines (trialkyl (C 1 -C ₆ ) amines) such as triethylamine, or heterocycles such as 1,4-diazabicyclo [2,2,2-octane ( DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), pyridine, diaminopyridine, methylpiperidine or morpholine. It is also possible to use alkali metals such as sodium or hydrides thereof such as sodium hydride as bases. Potassium carbonate, sodium hydride, potassium tert-butylate or cesium carbonate is preferred.

In general, the base is used in an amount of 0.05 to 10 mol, preferably 1 to 2 mol, based on 1 mol of the compound of formula III.

- 12GB 281937 B6

The process of the present invention is generally carried out at a temperature in the range of -100 to 100 ° C, preferably 0 to 80 ° C.

The process according to the invention is generally carried out at normal pressure, but it is also possible to work at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

Suitable catalysts are potassium iodide or sodium iodide, preferably sodium iodide.

The triphenylmethyl group is cleaved with acetic acid or trifluoroacetic acid and water or one of the abovementioned alcohols or with aqueous hydrochloric acid in the presence of acetone or with alcohols.

The cleavage is generally carried out at a temperature in the range of 0 to 150 ° C, preferably 20 to 100 ° C and at normal pressure.

The alkylation is generally carried out using alkylating agents such as, for example, C1 -C6 alkyl halides, sulfonic acid esters or substituted or unsubstituted C1 -C6 dialkyl sulfonates or diarylsulfonates, preferably methyl iodide or dimethyl sulfate.

The alkylation is generally carried out in one of the abovementioned solvents, preferably dimethylformamide, at a temperature in the range of 0 to 70 ° C, preferably 0 to 30 ° C and at normal pressure.

Suitable bases for saponification are conventional inorganic bases. These preferably include alkali metal or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide or barium hydroxide, alkali metal carbonates such as sodium carbonate, potassium carbonate or sodium bicarbonate, or alkali metal alcoholates such as sodium ethoxide , potassium ethoxide, sodium methoxide, potassium methoxide, or potassium tert-butoxide. Sodium hydroxide or potassium hydroxide is particularly preferred.

Suitable solvents for saponification are yoda or the organic solvents customary for saponification. These preferably include alcohols such as methanol, ethanol, propanol, isopropanol or butyl alcohol, ethers such as tetrahydrofuran or dioxane, or dimethylformamide or dimethyl sulfoxide. Alcohols such as, for example, ethanol, methanol, propanol or isopropyl alcohol are particularly preferably used. It is also possible to use mixtures of the solvents mentioned.

The saponification can also optionally be carried out with acids such as trifluoroacetic acid. acetic acid, hydrochloric acid, hydrobromic acid, methanesulfonic acid, sulfuric acid or perchloric acid, trifluoroacetic acid is preferred.

The saponification is generally carried out at a temperature in the range of 0 to 100 ° C, preferably 20 to 80 ° C.

In general, the saponification is carried out at normal pressure, but it is also possible to operate at elevated or reduced pressure, for example in the range of 0.5 to 5 bar.

In carrying out the saponification, the base is generally used in an amount of 1 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of ester. A molar amount of the reactants is particularly preferably used.

The saponification of tert-butyl esters is generally carried out with acids, such as hydrochloric acid or trifluoroacetic acid, in the presence of one of the abovementioned solvents and / or water, or a mixture thereof, preferably in the presence of dioxane or tetrahydrofuran.

- 13 GB 281937 B6

The amidation and sulfonamidation are generally carried out in one of the abovementioned solvents, preferably tetrahydrofuran or dichloromethane.

The amidation and sulfonamidation can take place via the activation stage of the acid halides, which can be prepared from the corresponding acids by reaction with thionyl chloride, fosfortrichloride, phosphorus pentachloride, fosfortribromide or oxalyl chloride.

The amidation and sulfonamidation are generally carried out at a temperature in the range of -20 to 80 ° C, preferably -10 to 30 ° C and under normal pressure.

Suitable bases for this purpose are, in addition to the abovementioned bases, in particular triethylamine and / or dimethylaminopyridine, DBU or DABCO.

The bases are used in an amount of 0.5 to 10 mol, preferably 1 to 2 mol, based on 1 mol of the corresponding acid or ester.

As acid-binding agents, alkali metal or alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkali metal or alkaline earth metal hydroxides such as sodium hydroxide 20 or potassium hydroxide, organic bases such as e.g. pyridine, triethylamine, N-methylpiperidine, or bicyclic amidines such as 1,5-diazabicyclo [3.4.0] nonen-5 (DBN) or 1,5-diazabicyclo [3.4.0] undecen-5 (DBU). Potassium carbonate is preferred.

Suitable dehydrating agents are carbodiimides, such as diisopropylcarbodiimide 25 or N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride. carbonyl compounds such as carbonyl diimidazole, 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-1,2-oxazolium-3-sulfonate, or further propanephosphonic anhydride, isobutyl chloroformate, benzotriazolyloxy-tris- (dimethylamino) phosphonium hexafluorophosphate, diphenyl ester phosphonic acid or methanesulfonic acid chloride, optionally in the presence of bases such as, for example, triethylamine, N-ethylmorpholine, dicyclohexylcarbodiimide and N-hydroxysuccinimide (see e.g.

J.C. Sheehan, S.L. LEdis, J. Am. Chem. Soc. 95, 875 (1973): F.E. Frerman et al., J. Biol. Chem. 225, 507 (1982) and N. Benoton, B. Kluroda, Int. Pept..Prot. Res. 13, 403 (1979), 17,187 (1981)].

The acid binding agents and dehydrating agents are generally employed in an amount of 0.5 to 3 mol, preferably 1 to 1.5 mol, based on 1 mol of the corresponding carboxylic acid.

The compounds of formula (II) are partly known or novel and in this case can be prepared analogously to known cases (see, for example, DE 3 406 329 A1, RP Mariella, 40 R. Stransfield, J. Am. Chem. Soc. 73, 1368). 1951 (and O. Isler et al., Helv Chim Acta 38, 1033 (1955)).

The compounds of formula III are known per se.

The above method of manufacture is given for clarity only. The preparation of the compounds of the formula I according to the invention is not limited to this process;

The substituted biphenylpyridones of the present invention exhibit an unexpectedly valuable spectrum of pharmacological effect. .

The compounds of the present invention have a specific A II-antagonistic effect by competitively or non-competitively inhibiting the binding of angiotensin II to receptors. They suppress the vasoconstrictor and aldosterone secretion-stimulating effects of angiotensin II. In addition, they inhibit

- 14GB 281937 B6 proliferation of smooth muscle cells.

They can therefore be used in medicaments for the treatment of arterial hypertonia and atherosclerosis. In addition, they may be used to treat coronary heart disease, cardiac insufficiency. brain performance disorders, cerebral ischemic diseases, peripheral blood flow disorders, renal and adrenal function disorders, bronchospastic and vascular diseases of the respiratory tract, sodium retention and edema.

Assay for inhibition of antagonist-induced contractions

Rabbits of both sexes are sacrificed in the back of the neck and bled, or optionally anesthetized with nembutal (about 60-80 mg / kg i.v.) and sacrificed by opening the thorax. Thoraxaorta is removed, removed from the tissues present, divided into 1.5 mm annular segments and treated individually in an 10 ml organ bath, tempered to 37 ° C, 15 Krebs-Henseleit nutrient solution at an initial load of about 3.5 g. carbon dioxide, of the following composition:

119 mM NaCl

2.5 mmol / l mmol / l

4.8 mmol / l

1.4 mmol / l mmol / l

CaCl ₂ x 2 H ₂ O glucose kci

MgSO ₄ x 7 H _; O a

NaHCO3.

Contractions are determined isometrically in Statham UC2 chambers via a bridge amplifier (ifd 25 Mohheim or DSM Aalen) and are digitized and evaluated using an A / D converter (System 570, Keithley München). The dose-dependent agonist (DWK) curves are run hourly. For each DWK, 3 or 4 individual concentrations are applied to the bath at 4 minute intervals. After completion of the DWK and subsequent growth cycles (about 5s / min each time with the above nutrient solution), a 28 minute resting or 30 incubation phase follows, during which the contractions usually reach the initial value again.

Height, normally 3. The DWK is used as a reference magnitude for the evaluation of the test substance tested in other processes, which is applied to the baths at the beginning of the incubation period at each increasing dose at subsequent DWKs. Each ring of aorta is stimulated with the same agonist all day 35.

Agonists and their standard concentrations / application volumes for a single dose = 100 μΐ:

KC1 noradrenaline serotonin B-HT 920 methoxamine angiotensin II

22.7; 32.7; 42.7; 52.7 mmol / lx10 ^-9 ; 3 x 10 '⁸; 3 x 10 '⁷; 3 x 10 · ⁶ g / ml

⁸ '⁸; ⁷ '⁷; 10 ⁶ ; 10 ^-5 g / ml

⁷ '⁷; ⁶ '⁶; 10 ^-5 g / ml

⁷ '⁷; 10 '⁶; l0 ^'3 g / ml x 10 ^9; 10 '⁸; 3 x ΙΟ'⁸; 10 ^-7 g / ml

To calculate an IC ₅₀ value (the concentration at which the test substance causes 50% inhibition), the effect on the 3 rd = submaximal antagonist concentration is taken as the basis.

The compounds of the present invention inhibit angiotensin II caused by rabbit aorta (isolated) contractions. depending on the dose. Contractions induced by potassium depolarization or other antagonists are not inhibited or are poorly inhibited at high concentrations.

- 15 GB 281937 B6

Table A

Inhibition of vascular contractions on isolated aortic rabbit rings in vitro

IC ₅₀ (g / ml) against A II-induced contractions

Ex. C. IC50 (nM) XCII 120 LXXVIII 34 XLIII 39 XLV 3.7 LIV 13 XXXIII 7.3 LXXIII 8.6

Blood pressure measurement in angiotensin II infused rats

Male Wistar rats (Moellegaard, Kopenhagen, Denmark) weighing 300-350 g are anesthetized with thiopental (100 mg / kg i.p.). Following tracheotomy, a blood pressure catheter is inserted into the femoral artery and an angiotensin II infusion catheter and a substance delivery catheter are inserted into the femoral vein. Angiotensin II infusion (0.3 pg / kg / min) is initiated after the administration of pentolinium blocking agent (5 mg / kg i.v.). When blood pressure reaches 1? stable levels, the test substances are administered either intravenously or as a suspension or solution in 0.5% tylose orally. The suppression of blood pressure due to the administered substance is presented in the following table as mean ± SEM.

Table

Ex. No. I 0.3 mg / kg p.o. blood pressure lower than 50 mm Hg

Determination of antihypertensive effect in alert hypertensive rats

The oral antihypertensive effect of the compounds of the present invention was tested in waking rats with surgically induced unilateral renal arteriestenosis. In addition, the right kidney artery is narrowed to 0.18 mm in diameter with a silver clip. In this form of hypertonia, plasma inactivity is increased in the first six weeks after the procedure.

The arterial pressure of these animals is measured bloodlessly at defined intervals after administration of the test substance by the tail cuff. The test substances are administered mixed in the tylosis suspension intragastrally (orally) by means of an oesophageal probe in different doses. Compounds 35 of the present invention reduce the arterial blood pressure of high pressure rats at clinically relevant doses.

In addition, the compounds of the present invention inhibit concentration-specific binding of radioactive angiotensin II in a concentration-dependent manner. Interactions of the compounds of the present invention with angiotensin II receptors on adrenal cortex membrane fractions (bovine)

The bark of the bovine adrenal glands (NNR), which have been freshly removed and carefully removed from the capsule residue, is ground into a coarse membrane homogenate using a Ultra-Turrax (Janke & Kunkel, Staufen i. B.) in a sucrose solution (0.32 M). In two centrifugation steps, 45 were partially purified to membrane fractions.

- 16GB 281937 B6

Receptor binding assays are performed on a 0.25 ml volume of purified bovine NNR with radioactive angiotensin II containing partially purified membranes (50-80 gg), ³ H-angiotensin II (3-5 nM), assay buffer solution (50 mM Tris, pH 7.2, 5 mM MgCl ₂ ) as well as the test substance. After an incubation time of 60 minutes at room temperature, 5 unbound sample is separated using a moistened glass filter (Whatman GF / C) and the bound radioactivity is measured spectrophotometrically after washing the protein with ice-cold buffer solution (50 mM Tris / HCl, pH 7.4, 5%). PEG 6000) in a scintillation cocktail. Analysis of the raw data was carried out using computer programs to give "or IC ₅₀ (K ,: IC ₃ -o, corrected for the radioactivity used; _IC50 values: concentration at which the test substances also caused 50% inhibition of specific binding of the radioligand).

The results are shown in the following table:

Table

Ex. C. K / nM XXXIV > 10,000 XLVII 220 XCIV 42 LV 15 Dec LVI 9 LXXXII 79

Smooth muscle cell proliferation inhibition assay by compounds of the invention

Smooth muscle cells obtained from the aorta of rats using the Media-Explanat technique (R. Ross, J. Cell. Biol. 50, 172, 1971) were used to determine the antiproliferative effect of the compounds. Cells are seeded in suitable culture flasks, typically 24-hole plates, and cultured for 2-3 days in 199 medium with 7.5% FCS and 7.5% NCS, 2 mM L-glutamine and 15 mM HEPES, pH 7 4 in 5% CO ₂ and at 37 ° C. Thereafter, the cells are synchronized by not providing serum for 2-3 days and then stimulated to grow with AII, serum and other factors. Simultaneously, the test compound is administered. After 16-20 hours, ³ H-thymidine is admixed, and after a further four hours of incorporation of this substance, the DNA of the cells precipitated in TCA is determined.

The novel active compounds can be converted into conventional preparations such as tablets, dragees, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, by known methods, using inert, non-toxic, pharmaceutically acceptable carriers or solvents. Here, the therapeutically active compound should always be present in a concentration of about 0.5 to 90% by weight of the total composition, i.e. in an amount sufficient to achieve the indicated dosage clearance.

For example, the preparations may be prepared by treating the active ingredient with solvents and / or carriers, optionally with emulsifiers and / or dispersing agents, whereby, for example, if water is used as a diluent, an organic solvent may optionally be used as a solubilizing aid.

Administration is effected by conventional means, preferably orally or parenterally, in particular perlingually or intravenously.

For parenteral administration, solutions of the active ingredient using suitable liquid carrier materials may be employed.

- 17GB 281937 B6

In general, it has proven advantageous to administer an amount of about 0.001 to 1 mg / kg, preferably about 0.1 to 0.5 mg / kg body weight, for intravenous administration to achieve effective results, and for oral administration a dosage of about 0.01 to 20 mg / kg, preferably 0.1 to 10 mg / kg body weight.

Nevertheless, it may be desirable to withdraw these amounts, depending on the body weight or the type of administration, the individual drug tolerance, the type of formulation and the time or interval at which the administration takes place. Thus ^- in some cases it is sufficient to start from less than the minimum quantities mentioned above, while in other cases the upper limit mentioned must be exceeded. In the case of administration of larger amounts, it is advisable to divide these into a number of individual doses.

DETAILED DESCRIPTION OF THE INVENTION

Starting compounds

Example 1

6-Butyl-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine

H ₃ C- (CH ₂ ) ₃

H

To a suspension of 29.25 g (0.15 mol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 200 ml of methanol was added dropwise 12.5 ml (0.17 mol) of thionyl chloride under stirring and ice-cooling. and the reaction mixture was further stirred at room temperature overnight. It is then concentrated to dryness and the residue is chromatographed on 450 g of silica gel [0.066-0.038 mm (230-400 mesh)] with dichloromethane → dichloromethane / methanol 10: 1. 29.6 g (94%) of colorless crystals crystallize from dichloromethane, ether and petroleum ether of crystals.

Melting point: 106 ° C.

The compounds listed in Table 1 were prepared analogously to Example 1.

- 18GB 281937 B6

Table 1

Ex. C. R ¹ R m.p. (° C) yield (% theor.) default merge CO-H AND H R ¹ 2 -nC ₄ H ₉ -C ₂ H ₅ 98 97 -nC ₄ H ₉ 3 -nC ₄ H ₉ -CH (CH _{3) 2} 127 86 -n-C4Hg 4 -nC ₃ H ₇ -ch ₃ 144 88 -nC ₃ H ₇ 5 -nC ₃ H ₇ -c ₂ h ₅ 129 93 -nC ₃ H ₇ 6 -c ₂ h ₅ -ch ₃ 192 85 -C ₂ H ₅ 7 O- -ch ₃ 191 35 D> - . 8 -n-CsHn -ch ₃ 100 ALIGN! 87 -n-CsHii 9 -ch ₃ * -C ₂ H ₃ 184-186 -CH ₃

* In contrast to the procedure of Example 1, ethanol or isopropyl alcohol was used instead of methanol and stirred overnight at 50 ° C.

Example 10

6-Buty-2-oxo-1,2-dihydropyridine

H ₃ C- (CH 2) ₃

H

4.9 g (25 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid are refluxed (237 ° C) with 1.79 g (12.5 mmol) of cuprous oxide in 50 ml quinoline for 1.5 hours.

After filtration, the volatile components were distilled off in vacuo (110 ° C at 1.7 kPa, then 67 ° C at 0.9 kPa). The residue is chromatographed twice with dichloromethane / methanol (40: 1) -> (20: 1) and the product is triturated in petroleum ether.

Yield: 1.95 g (52%) of brownish crystals, m.p. 68 ° C.

- 19GB 281937 B6

Example 11

6-Butyl-4-benzyloxycarbonyl-2-oxo-1,2-dihydropyridine

H

To a solution of 6.0 g (31 mmol) of 6-butyl-2-oxo-1,2-dihydro-isonicotinic acid in 100 ml of dimethylformamide was added 13.3 g (123 mmol) of benzyl alcohol and 4.7 g (31 mmol). hydroxybenzotriazole. The resulting clear solution was cooled to 0 ° C, followed by the addition of 7.0 g (34 mmol) of dicyclohexylcarbodiimide and 4.2 mL (31 mmol) of triethylamine. The reaction was allowed natát at 20 ^e C, it is stirred for 2 hours and then treated with aqueous procedure. 6.8 g (77% of theory) of the title compound are obtained.

Melting point: 139 ° C.

Example 12

6-Propyl-2-oxo-1,2-dihydropyridine

Analogously to Example 10, 71% of the title compound is obtained, m.p. 89-90 ° C.

Example 13

6-Butyl-4-carbamoyl-2-oxo-1,2-dihydropyridine

B6 g (14.3 mmol) of the compound of Example 1 was heated in 10 ml of ethanol and 20 ml of concentrated ammonia for several minutes. An additional 5 ml of ammonia is then added three times and the mixture is briefly heated to boiling again. After cooling, the precipitate formed is filtered off with suction and dried over phosphorus pentoxide in vacuo.

Yield: 1.19 g (43% of theory), m.p. = 290 DEG C. (decomposition).

Example 14

4-Carbamoyl-2-oxo-6-propyl-1,2-dihydropyridine

Analogously to Example 13, the title compound was obtained from colorless crystals in 66% yield.

Melting point: > 280 ° C.

Example 15

4-Benzylcarbamoy 1-6-butyl-oxo-1,2-dihydropyridine

Analogously to Example 11, using two molar equivalents of benzylamine instead of benzyl alcohol and triethylamine, the title compound is obtained in colorless crystals in 47% yield.

Temperature: 177 ° C.

-21 GB 281937 B6

Example 16

4-Benzylcarbamoyl-2-oxo-6-propyl-1,2-dihydropyridine

Analogously to Example 15, the title compound is obtained in the form of colorless crystals from 2-oxo-6-propyl-1,2-dihydroisonicotinic acid in 44% yield. Melting point: 210 ° C.

Example 17

3-Cyano-4,6-dipropyl-2-oxo-1,2-dihydropyridine

15.6 g (0.1 mol) of 4.6-Nonadione are refluxed with 8.4 g (0.1 mol) of cyanacetamide and 13.8 g (0.1 mol) of potassium carbonate in 100 ml of acetone for 4 hours. hours. The acetone is then stripped off in vacuo, the residue is suspended in 250 ml of water, acidified with concentrated hydrochloric acid to pH 1-2, the precipitate formed is filtered off with suction, washed with water and dried over phosphorus pentoxide in vacuo.

Yield: 18.2 g (89%) of colorless crystals, m.p. 148 ° C.

Example 18

6-Butyl-3-cyano-4-methyl-2-oxo-1,2-dihydropyridine

-22EN 281937 B6

Analogously to Example 17, the title compound is obtained in 94% yield, m.p. 144-148 ° C, from 2,4-octadione. The product contains about 15% isomeric 4-butyl-3-cyano-6-methyl-pyrid-2 (1H) -one as a contaminant.

Example 19

4,6-Dipropyl-2-oxo-1,2-dihydropyridine

13.1 g (64 mmol) of the compound of Example 17 was refluxed in 22 ml of water and 22 ml of concentrated sulfuric acid for 4 hours. The pH is then adjusted to about 6 with sodium carbonate, the oily substance is taken up in ethyl acetate, the organic phase is washed with saturated sodium chloride solution and dried over sodium sulphate. After removal of the solvent, it is dried under high vacuum.

Yield: 9.5 g (83%) of a yellowish solid, mp 62 ° C.

Example 20

6-Buty-1-4-methyl-2-oxo-1,2-dihydropyridine

H

Analogously to the previous example, the title compound is obtained from the compound of Example 18.

Melting point: 95 ° C.

The product contains about 10% isomeric 4-butyl-6-methyl-pyrid-2 (1H) -one as an impurity.

-23GB 281937 Β6

Example 21

4-Hydroxymethyl-6-propyl-2-oxo-1,2-dihydropyridine

To a suspension of 3.0 g (16.6 mmol) of 2-oxo-6-propyl-1,2-dihydroisonicotinic acid was added dropwise at 0 ° C 27.8 ml and after one hour at room temperature again 27.8 ml. A 1M solution of boron hydride in tetrahydrofuran and stirred for an additional hour at room temperature. To the now clear solution was added dropwise 66.8 ml of 1N hydrochloric acid and 100 ml of water, the reaction mixture was stirred for one hour at room temperature and extracted three times with 75 ml of ethyl acetate each time. The organic phase is drained, the aqueous phase is basified to a pH of about 7 with saturated sodium bicarbonate solution and the precipitate is filtered off with suction. The aqueous filtrate is evaporated to dryness and the residue is crystallized from about 80 ml of water together with the first precipitate. 1.28 g (46%) of product are obtained as colorless crystals.

Melting point: 167 ° C.

Example 22

2-Benzoyloxy-4-benzoyloxymethyl-6-propyl-pyridine

To a suspension of 1.26 g (7.5 mmol) of the compound of Example 21 in 40 mL of tetrahydrofuran at about 10 ° C was added 3.1 mL (22.6 mmol) of triethylamine, 0.28 g (2.3 mmol). Of 4-dimethylaminopyridine and 1.3 ml (11.3 mmol) of benzoyl chloride and the mixture is stirred for 3 hours at room temperature. 50 ml of water are then added, extracted three times with 30 ml of ethyl acetate each time, the combined organic phases are washed with saturated sodium hydrogen carbonate solution, citric acid solution and sodium hydrogen carbonate solution, dried over sodium sulphate and concentrated. The residue is chromatographed on 40 g of silica gel [0.066-0.038 mm (230-400 mesh)] using dichloromethane-ethyl acetate 100: 1 - 20: 1.

Yield: 1.67 g (59%) of a colorless solid.

_Rf = 0.73 (dichloromethane-ethyl acetate 20: 1).

-24GB 281937 B6

Example 23

6-Propyl-3,5-diethoxycarbonyl-2-oxo-1,2-pyridine

0 (¾

62.8 g (0.4 mol) of 3-amino-2-hexenoic acid ethyl ester and 86.4 g (0.4 mol) of ethoxymethylenemalonic acid diethyl ester are stirred for 40 hours at 100 ° C. The mixture was cooled to 20 ° C, the solid was filtered off with suction and crystallized from ethanol.

Yield: 36.2 g (32.2% of theory), @ 1 H-NMR (CDCl3) .delta. = 1.05 (t, 3H), 1.4 (dt, 6H), 1.8 (m, 2H), 3.15 (t, 2H), 4.35 (m, 4H), 8.8 (s, 1H), 13.1 (s, 1H) ppm.

Example 24

5-Ethoxycarbonyl-3-methoxycarbonyl-2-oxo-4-phenyl-6-propyl-1,2,3,4-tetrahydropyridine

och ₃

26.2 g (0.128 mol) of ethyl benzylidene malonic acid and 20.1 g (0.128 mol) of ethyl 3-amino-2-hexenoate were stirred with a small amount of sodium ethylate for 3 days at 140 ° C. The product is chromatographed on silica gel using methylene chloride and crystallized from petroleum ether.

Yield: 6.7 g (15% of theory).

Rf = 0.47 (ethyl acetate / petroleum ether 1: 1).

-25 GB 281937 B6

Example 25

5-Ethoxycarbonyl-3-methoxycarbonyl-2-oxo-4-phenyl-6-propyl-1,2-dihydro-pyridine

och ₃

5.7 g (16.5 mmol) of the compound of Example 24 and 18.0 g (33 mmol) of cerammonium nitrate are stirred in 100 ml of acetonitrile and 50 ml of water overnight at 20 ° C, then acetonitrile is added. After distillation, the aqueous phase is washed with methylene chloride, the organic phase is washed with water, dried over sodium sulphate and concentrated.

Yield; 5.0 g (88% of theory).

Rf = 0.19 (ethyl acetate / petroleum ether 1: 1).

Example 26

5-Ethoxycarbonyl-2-oxo-4-phenyl-6-propyl-1,2,3,4-tetrahydropyridine

8.7 g (25 mmol) of the compound of Example 24 and 1.5 g of sodium chloride are stirred overnight in 25 ml of dimethyl sulfoxide and 1.2 ml of water at 180 ° C. Then the reaction mixture was cooled to 20 ° C, poured into water and washed with ethyl acetate. The organic phase was washed with water and dried over anhydrous sodium sulfate.

Yield: 3.9 g (67% of theory).

Rf = 0.45 (petroleum ether / ethyl acetate 2: 1).

-26GB 281937 B6

Example 27

5-Ethoxycarbonyl-2-oxo-4-phenyl-6-propyl-1,2-dihydropyridine

Analogously to Example 25, 6.5 g of the compound of Example 26 was reacted to give the title compound

3.6 g of the title compound.

Yield: 56%.

R _f = 0.21 (petroleum ether / ethyl acetate 1: 1).

Example 28

6-Butyl-3,4-bis-ethoxycarbonyl-2-oxo-1,2-dihydropyridine

g (50 mmol) of 2,4-dioxo-octanecarboxylic acid ethyl ester, 5.65 g (50 mmol) of ethyl cyanoacetate and 5 g (50 mmol) of triethylamine were heated at reflux overnight in 100 ml of ethanol.

The solvent is then distilled off, the residue is dissolved in methylene chloride, washed with dilute hydrochloric acid and water, and the organic phase is dried over sodium sulphate. Chromatograph on silica gel using methylene chloride / methanol gradient.

Yield: 8.8 g (60% of theory).

MS (DCI): 296 (M + H) < + >.

-27GB 281937 B6

Example 29

6-Ethyl-3,5-diiodo-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine

COOMe

A solution of 6-ethyl-3,5-diiodo-4-carboxy-2-oxo-1,2-dihydropyridine (0.10 g, 0.24 mmol) in thionyl chloride (1.1 mL) was heated at rt for 3 h. 80 ° C, then concentrated and refluxed for one hour after addition of methanol (5 ml). After concentration, partitioning of the residue between ethyl acetate ^- sodium bicarbonate solution and drying of the organic phase with saturated sodium chloride solution and anhydrous sodium sulphate, after concentration, 0.10 g of product is obtained as a solid (96% of theory).

Rf = 0.43 (methylene chloride / methanol / formic acid 10: 1: 0.1).

MS (EI): 433 (100%; M).

Example 30

6-Butyl-3,5-diiodo-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid methyl ester

A solution of 6-butyl-1,2-dihydro-3,5-diiodo-2-oxo-pyridine-4-carboxylic acid (50 g; 0.11 mol) in dimethylformamide (250 mL) at 0 ° C was treated with potassium carbonate (17 g; 0.12 mol) and a solution of methyl iodide (6.7 ml; 0.11 mol) in dimethylformamide (50 ml) and then stirred at room temperature overnight. The reaction solution is then concentrated, the residue is taken up in ethyl acetate and washed with potassium hydrogen sulphate solution, sodium carbonate solution and saturated sodium chloride solution. After drying and concentration of the organic phase, 30 g of a yellow solid (58% of theory) are obtained by chromatography on silica gel (methylene chloride / ethyl acetate 10: 1).

Rf = 0.47 (methylene chloride / ethyl acetate 20: 1).

MS (DC1). 336 (100%, M + H).

-28GB 281937 B6

Example 31

6-Butyl-3,5-diiodo-4-methoxycarbonyl-2-oxo-3- (2-phenylethenyl) -1,2-dihydropyridine

A solution of the compound of Example 30 (3.0 g; 6.5 mmol) in N-methylpyrrolidin-2-one was treated with palladium acetate (15 mg; 0.065 mol), tributylamine (1.6 mL; 6.5 mL) under argon. mmol) and styrene (0.82 mL; 7.2 mmol) and heated at 80 ° C for 48 hours. Then tributyltin (5.3 mL; 20 mmol) was added and stirred overnight at 80 ° C, tetrakis (triphenylphosphine) palladium (1.2 g; 1.0 mmol) was added and stirred again at night temperature 80 ° C. The reaction solution was then concentrated, partitioned between ethyl acetate and potassium hydrogen carbonate solution, the organic phase was dried and concentrated and the residue was chromatographed on silica gel (hexane / ethyl acetate 3: 1).

Yield: 0.49 g (23% of theory) of a yellow resin.

Rf = 0.20 (hexane / ethyl acetate 3: 1).

MS (DCI): 312 (100%, M + H).

The compounds listed in Table 2 were prepared analogously to Example 17.

Table 2

R ³

Ex. R ¹ R ² R ³ R ⁴ m.p. [° C] Edukt 32 CH ₃ OCH ₂ - H -COOCH3 -CN 200-203 (dec.) OO II II CH ₃ OCH ₂ C-CH ₂ C-COOCH ₃ 33 (CHjhCH- H -COOCH ₂ CH ₃ -CN 191 OO II II (CH ₃ ) ₂ CH-CCH ₂ C-COOCH ₂ CH ₃

The compounds listed in Table 3 were prepared analogously to Examples 1 and 19.

-29GB 281937 B6

Table 3

R ³

Ex. R ¹ R- R ^J R ⁴ m.p. [° C] Edukt / př. C. 34 CH ₃ OCH ₂ - H -cooch ₃ H 165 32 35 _{(CH3) 2} CH-, H -cooch ₃ H 188

The following compounds, listed in Table 4, were prepared by the procedures given in this Table.

Table 4

Ex. R ¹ • R ² R ^J R ⁴ yield. (% theor.) R _f * Edukt / ex, No ** according to example no. 36 nC ₃ H- -COOCH ₂ CH ₃ H -COOH 55 0.15 .23 CV • 37 nC ₃ H _T -cooch ₂ ch ₃ H H 28 0.46 36 10 38 nC ₄ H ₉ -H H -COOH 86 0.45 2) konz. HCl / 10 0 39 nC ₄ H ₉ -H H -COOCH, 95 0.64 38 1

* Solvent Mixtures:

^υ dichloromethane / methanol 20: 1 ** starting material ²¹ 3-cyano-6-butyl-pyrid-2 (1H) -one

-30GB 281937 B6

Example 40

6-Butyl-4-cyano-2-oxo-1,2-dihydropyridine

H

4.6 g (24 mmol) of the compound of Example 13 are suspended in 50 ml of dioxane, 3.6 ml (26 mmol) of trifluoroacetic anhydride are added dropwise at about 10 ° C and the reaction mixture is stirred for 6 hours at room temperature. 150 ml of dichloromethane are then added, the precipitate is filtered off, the filtrate is washed with water and saturated sodium chloride solution, dried over anhydrous sodium sulphate and concentrated. The residue was treated with diethyl ether and filtered.

Yield: 2.03 g (52% of theory) of colorless crystals.

Melting point: 173 ³ C.

Example 41

6-Butyl-2-oxo-4- (tetrazol-5-yl) -1,2-dihydropyridine

N - NH

1 «I

H3C. J | \ ΔΑν ^Λ ο

H

1.6 g (9.7 mmol) of the compound of Example 40 is stirred with 6.97 g (50.7 mmol) of triethylammonium hydrochloride and 3.29 g (50.7 mmol) of sodium azide in 100 ml of dimethylformamide for 18 hours at an internal temperature of about 130 ° C behind the protective plate. The reaction mixture is evaporated to dryness, about 400 g of ice are added and acidified to pH 1.2 with 1N sulfuric acid. It is extracted three times with 400 ml of ethyl acetate each time, the combined organic phases are dried over anhydrous sodium sulphate and evaporated. The residue was crystallized from dichloromethane, ether and petroleum ether.

Yield: 1.93 g (90% of theory) of colorless crystals, m.p. 227 DEG.

-31 GB 281937 B6

Example 42

6-Butyl-2-oxo-4- (N-triphenylmethyl-tetrazol-5-yl) -1,2-dihydropyridine

N - NC (C ₆ H ₅ ) ₃

1.0 g (4.6 mmol) of the compound of Example 41 was dissolved in 30 mL of dichloromethane and refluxed with 1.46 mL (5.4 mmol) of triphenylmethyl chloride and 0.8 mL (5.8 mmol) of triethylamine. for 2 hours. The reaction mixture was washed with water and saturated sodium chloride solution, concentrated to dryness, and the residue was crystallized from dichloromethane / diethyl ether / petroleum ether.

Yield: 1.73 g (82%) of colorless crystals, m.p. 208 DEG C. (decomposition).

Manufacturing examples

Example I

6-Butyl-4-methoxycarbonyl-2-oxo-1- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) methyl) 1,2-dihydropyridine

H ₃ C- (CH 2) ₃

Method A

20.92 g (0.1 mol) of the compound of Example 1 are dissolved in 200 ml of dimethylformamide, treated portionwise with 13.5 g of potassium butylate target and stirred for 10 minutes at room temperature. A solution of 55.75 g (0.1 mol) of N-triphenylmethyl-5- [2- (4 ' -bromomethylbiphenyl) tetrazole in 200 ml of dimethylformamide is then added dropwise and the reaction mixture is stirred overnight at room temperature. 500 ml of water are then added dropwise, extracted three times with 300 ml of ethyl acetate each time

The combined organic phases are dried over sodium sulphate and concentrated. The residue is chromatographed on silica gel (450 g, [0.061-0.038 mm, 250-400 mesh]) using a petroleum ether / ethyl acetate gradient of 5: 1 → 1: 2.

Yield: 9.69 g (14%) of a colorless foam.

Rf = 0.3 (petroleum ether / ethyl acetate 2: 1).

Method B

To a solution of 31.4 g (0.15 mmol) of the compound of Example 1 in 600 mL of dimethoxyethane was added 61.1 g (0.188 mol) of cesium carbonate, stirred for 15 minutes at room temperature, then 100.4 g. (0.18 mol) of N-triphenylmethyl-5- [2- (4'-bromomethyl-biphenyl)] tetrazole was stirred overnight at room temperature and then refluxed for 3 hours.

The reaction mixture was then partitioned between water and ethyl acetate (ca. 0.8 L each), the organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated. The residue was filtered through 2 kg of silica gel (0.046-0.038 mm (230-400 mesh)) using petroleum ether / ethyl acetate 5: 1 -> 1: 1.

Yield: 39.8 g (38.6%) of a yellow amorphous solid.

Rf = 0.3 (petroleum ether / ethyl acetate 2: 1).

About 70 g of crude 6-butyl-4-methoxycarbonyl-2- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) -methoxy-pyridine is isolated as a by-product.

Rf = 0.78 (petroleum ether / ethyl acetate 2: 1).

Analogously to procedures A and B for the compounds of Example 1, the compounds shown in Table I are obtained.

-33 GB 281937 B6

Table I

Ex. C. R ¹ R ³ R ⁴ yield (% of theor.) R _t * Educt / Method A / B II -n-C-tHo ΡΓ H 14 0.16 10 / A III -c ₂ h ₅ -C ₂ H ₅ CN 20 May 0,12 ¹¹ AND IV -n-CjHo -co ₂ c ₂ h ₅ H 16 0.40 2 / B IN -nC ₄ H ₉ -CO ₂ CH (CH ₃ ) ₂ H 34 0.48 3 / B VI -nC ₃ H ₇ - about ₂ ch ₃ H 26 0.24 4 / B VII -nC ₃ H- -co ₂ c ₂ h ₅ H 25 0,29 ¹¹ 5 / B VIII -C ₂ H ₅ - about ₂ ch ₃ H 25 0.15 6 / B IX - <] - about ₂ ch ₃ H 39 0.12 7 / B X -n-C 11 H 11 - about ₂ ch ₃ H 33 0.29 8 / B XI -ch ₃ -co ₂ c ₂ h ₅ H 41 0.18 9 / B XII -11-C4H9 -co ₂ -ch ₂ c ₆ h ₅ H 30 0.40 11 / B XIII -nC ₃ H ₇ H H 13 0.08 12 / B XIV -nC ₄ H ₉ -CONH, H 20 May 0,33 ²⁾ 13 / B XV -nC ₄ H ₉ -conh-ch ₂ c ₆ h ₅ H 27 Mar: 0.11 15 / B XVI -nC ₄ H ₉ -co ₂ c ₂ h ₅ CN 19 Dec 0.19 (B) XVII -nC ₃ H ₇ -co ₂ c ₂ h ₅ CN 21 0.07 (B) XVIII -c ₂ h ₅ -co ₂ c ₂ h ₅ CN 14 0.11 (B) XIX - < -co ₂ c ₂ h ₅ CN 5 0.15 (B) XX -nC ₃ H ₇ H CN 10 0.16 3-cyano-6-propylpyrid-2-one (A) XXI -nC ₃ H ₇ -nC ₃ H ₇ CN 44 0.2 17 / B XXII -nC ₄ Ho -ch ₃ CN 22nd 0.19 18 / B XXIII -nC ₃ H ₇ -nC ₃ H ₇ H 30 0.17 19 / B XXIV -nC ₄ H ₉ -ch ₃ H 23 0.14 20 / B XXV -nC ₃ H ₇ -ch ₂ o-co-c ₆ h ₅ H 13 0.21 22 / B XXVI -nC ₃ H ₇ -conh ₂ H 14 0,5 ³ * 14 / B XXVII -nC ₃ H ₇ -co ₂ -nhch ₂ -c ₆ h ₅ H 16 0.16 ³ ' 16 / B

* moving phase:

ⁿ petro ether / ethyl acetate 2: 1 ²⁾ dichloromethane / methanol 10: 1 ³⁾ petroleum ether / ethyl acetate 1: 1

-34GB 281937 B6

Example XXVIII

6-Butyl-4-hydroxymethyl-2-oxo-1- (2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl / methyl) -1,2-dihydropyridine

OH

A 3.5 molar solution of sodium bis (2-methoxyethoxy) dihydroaluminate in toluene was diluted 1:10 with tetrahydrofuran to give a 0.35 molar solution. 43 ml of this solution (15 mmol) is added dropwise at 0 ° C to a solution of 6.86 g (10 mmol) of the compound of Example I in 25 ml of tetrahydrofuran and stirred for one hour at 0 ° C and then for three hours at 0 ° C. room temperature. The reaction mixture was then re-cooled to 0 ° C, an additional 14.3 mL (5 mmol) of aluminate solution was added dropwise and stirred overnight at room temperature.

Water is then carefully added dropwise until gas evolution is complete and acidified with 6N hydrochloric acid to a pH of about 7. The combined filtrates are extracted with water and saturated sodium chloride solution, the organic phase is dried over sodium sulphate and concentrated. The residue is chromatographed on 200 g of silica gel [0.066-0.038 mm (230-400 mesh)] using dichloromethane / ethyl acetate (10: 1) (1-2).

Yield: 3.82 g (58%) of a colorless foam.

Rf = 0.37 (dichloromethane / methanol 10: 1).

Example XXIX

6-Butyl-4-methoxymethyl-2-oxo-1- (2 '- (N-triphenylmethyltetrazol-5-yl) biphenyl-4-yl / methyl) -1,2-dihydropyridine

-35 GB 281937 B6

To a suspension of 31.5 mg (1.05 mmol) of 80% sodium hydride in 5 mL of tetrahydrofuran was added dropwise under argon at 0 ° C 658 mg (1 mmol) of the compound of Example I and the reaction mixture was stirred for 10 minutes at at this temperature. A solution of 142 mg (1 mmol) of methyl iodide in 2 ml of tetrahydrofuran was then added dropwise and stirred for 3 days at room temperature. The reaction mixture is then treated with about 50 ml of water, extracted three times with 30 ml of ethyl acetate, the combined organic phases are dried over anhydrous sodium sulphate and concentrated to dryness. The residue is chromatographed on 18 g of silica gel [0.066-0.038 mm (230-400 mesh)] with dichloromethane → dichloromethane / ethyl acetate 1: 2.

Yield: 371 mg (55%) of a colorless foam.

Rf = 0.47 (dichloromethane / ethyl acetate 3: 1).

Example XXX

4-Butyl-6-methyl-2-oxo-1- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl / methyl) -1,2-dihydropyridine

The title compound is eliminated as a by-product in 3% yield by chromatography (silica gel, petroleum ether / ethyl acetate 1: 1) as a by-product.

R _f = 0.42 (petroleum ether / ethyl acetate 1: 1).

Example XXXI

6-Butyl-4-dimethylcarbamoyl-2-oxo-1- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) methyl) 1,2-dihydropyridine

281937 B6 mL (6 mmol) of a 2M solution of trimethylaluminum in toluene was diluted with 5 mL of toluene under an argon atmosphere. 0.44 ml (0.3 g, 6.6 mmol) of condensed dimethylamine is added dropwise at -10 ° C to -15 ° C and the reaction mixture is stirred for 15 minutes at -15 ° C. for 45 minutes at room temperature. A solution of 2 g (3 mmol) of the compound of Example I in 5 ml of toluene is then added dropwise and the reaction mixture is refluxed for 2 hours.

After cooling, the reaction mixture is carefully mixed with 50 ml of water and 7 ml of 1N hydrochloric acid, the suspension is stirred vigorously for 15 minutes and then extracted twice with ethyl acetate. The organic phases are washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated.

The residue is chromatographed on 50 g of silica gel [0.066-0.038 mm (230-400 mesh)] using dichloromethane / methanol 40: 1 → 10: 1.

Yield: 0.86 g (41%) of a yellowish foam.

R _f = 0.7 (dichloromethane / methanol 10: 1).

Example XXXII

6-Butyl-4-methoxycarbonyl-2-oxo-1 - ((2 '-tetrazol-5-yl-biphenyl-4-yl) methyl) -1,2-dihydropyridine

Method A

A solution of 3.0 g (4.37 mmol) of the compound of Example I in 40 ml of acetone was stirred with 0.4 ml of 37% hydrochloric acid for 30 minutes at room temperature and then heated on a water bath for about 1 minute. After the addition of an additional 0.4 ml of 37% hydrochloric acid, the process is repeated.

The reaction mixture is concentrated to dryness and the residue is chromatographed on 90 g of silica gel [0.066-0.038 mm (230-400 mesh)] using dichloromethane-dichloromethane / methanol 50: 1 → 10: 1.

Yield: 1.045 g (54%) of a colorless foam.

-37GB 281937 B6

Method B g (7.3 mmol) The compound of Example I was suspended in 35 mL of methanol and treated with 2.5 mL of concentrated hydrochloric acid to give a clear solution. The solution is stirred for 3 hours at room temperature, the precipitate is filtered off, washed with methanol and dried under vacuum over phosphorus pentoxide.

Yield: 2.6 g (80.3%) of a colorless solid, m.p. 209 DEG C. (decomposition).

MS (FAB) = 444 (100%, M + H), 235 (93%).

Analogously to Example XXXII (Methods A and B), the compounds listed in Table II were prepared.

Table II

Ex. C. R ' R ³ R ⁴ yield (% of theory) / method MS (FAB / DC2) Edukt XXXIII -nC ₄ H ₉ H H 27 / A 424 (50%, M + H); 386 (100%, M + H) II XXXIV -C ₂ H ₅ -C2H5 CN 58 / A 387 (100%, M + H) 412 (70%, M + H) III XXXV -nC ₄ H ₉ -CO ₂ C ₂ H ₅ H 19 / A 412 (70%, M + H) rv XXXVI -nC ₄ H ₉ -CO ₂ CH (CH ₃ ) ₂ H 67 / B 471. (100%, M + H) IN XXXVII -nC ₃ H ₇ - about ₂ ch ₃ H 44 / A 430 (100%, M + H) VI XXXVIII -nC ₃ H ₇ -co ₂ c ₂ h ₅ H 51 / A 445 (100%, M + H) VII XXXIX -C2H5 - about ₂ ch ₃ H 67 / A 417 (100%, M + H) VIII XL - <1 - about ₂ ch ₃ H 70 / A IX XLI -n-CsHu - about ₂ ch ₃ H 71 / B 457 (100%, M + H) X XLII -ch ₃ -co ₂ c ₂ h ₅ H 73 / B XI XLIII -nC ₄ H ₉ -CO ₂ CH ₂ -C ₆ H ₅ H 53 / A 520 (100%, M + H) XII XLIV -nC ₃ H ₇ H H 75 / A 371 (100%, M + H) XIII XLV -nC ₄ H ₉ -conh ₂ H 75 / A 429 (100%, M + H). XIV XLVI -nC ₄ H ₉ -co-nh-ch, c ₆ h ₅ H 65 / A 518 (100%, M + H) XV XLVII -nC ₄ H ₉ -co ₂ c ₂ h ₅ -CN 51 / A 484 (50%, M + H) 240 (100%, M + H) XVI XLVIII -nC ₃ H ₇ -co ₂ c ₂ h ₅ -CN 39 / A 467 (50%, M + H) 240 (100%, M + H) XVII

-38GB 281937 B6

Table II (continued)

Ex. C. R. ' R ³ R ⁴ yield (% of theory) / method MS (FAB / DC2) Edukt XLIX -c, h ₅ -CO ₂ C ₂ H ₅ -CN 38 / A ' XVIII L - < -co ₂ c ₂ h ₅ -CN 45 / A 466 (60%, M + H) 294 (100%) XIX IF -nC ₃ H ₇ H -CN 42 / A 394 (100%), M + H) 240 (100%) XX Lil -nC ₄ H ₉ -ch ₃ -CN 47 / A 425 (59%, M + H) 240 (100%) XII Lili -nC ₃ H ₇ -nC ₃ H ₇ -CN 52 / A 438 (90%, M + H) 240 (100%) XI LIV -nC ₄ H ₉ -CH ₂ OH H 93 / A 417 (100%, M + H) XXVIII LV -nC ₄ H ₉ -ch ₂ and ₃ H 59 / A 430 (100%, M + H) XXIX LVI -nC ₃ H ₇ -co-nh ₂ H 67 / A 415 (100%, M + H) &apos; XXVI LVII -nC ₃ H ₇ -CONH-CFLc ₆ H ₅ H 43 / A 504 (100%, M + H) XXVII LVIII -nC ₃ H ₇ -CH, -O-CO- c ₆ h ₅ H 60 / A 507 (70%, M + H) XXV LIX -nC ₄ H ₉ -ch ₃ H 48 / A 400 (90%, M + H) XXIV LX -CH ₃ -nC ₄ H ₉ H 46 / A 400 (70%, M + H) XXX LXI -nC ₃ H ₇ -nC ₃ H ₇ H 69 / A 414 (M + H, 100%) XXI LXII -nC ₄ H ₉ -CO-N _{(CH3) 2} H 74 / B 456 (100%, M + H) XXXI

Example LXIII

4-Hydroxymethyl-2-oxo-6-propyl-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

120 mg (0.24 mmol) of the compound of Example LVIII was stirred in 6 mL of methanol containing 14 mg (0.26 mmol) of sodium ethylate for one hour at room temperature. After addition of 0.28 ml of 1N hydrochloric acid, the reaction mixture is concentrated and the residue is chromatographed on 10 g of silica gel with dichloromethane / methanol 20: 1 → 5: 1.

Yield: 92 mg (97%) of a colorless foam. FAB-MS: 402 (100%, M + H).

-39GB 281937 B6

Example LXIV

6-Buty 1-4-methylcarbamoy 1-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl 1-4-yl) methyl] -1,2-dihydropyridine

CH ₃ t ^J

0.67 g (1.5 mmol) of the compound of Example XXXII was refluxed in 7.5 ml of tetrahydrofuran, 2.5 ml of methanol and 5 ml of a 40% aqueous methylamine solution for 10 minutes. Concentration and filtration through 50 g of silica gel using dichloromethane / methanol (5: 1) gave 0.56 g (84%) of an amorphous colorless solid.

FAB-MS: 443 (80%. M + H).

Example LXV

6-Butyl-4-cyclopropylcarbamoyl-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

0.67 g (1.5 mmol) of the compound of Example XXXII is refluxed in 10 ml of cyclopropylamine for 4 hours, after removal of the amine, the residue is dissolved in 5 ml of tetrahydrofuran and 5 ml of methanol, mixed with 0.33 μΐ concentrated The residue is chromatographed on 20 g of silica gel with dichloromethane / methanol 5: 1.

Yield: 0.48 g (68%) of an amorphous solid.

FAB-MS: 469 (90%, M + H) &lt; + &gt;.

-40GB 281937 B6

Example LXVI

2-Phenylethylammonium salt 6-butyl-2-oxo-4- (2-phenylethylcarbamoyl) -1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2,2- dihydropyridine

215 mg (0.5 mmol) of the compound of Example LXX was dissolved with 181 mg (1.5 mmol) of 2-phenylethylamine and 77 mg (0.5 mmol) of hydroxybenzotriazole in 10 ml of dimethylformamide and mixed at 0 ° C. 106 mg (0.55 mmol) of N- (3-dimethylaminopropyl) -N-ethylcarbodiimide hydrochloride were added and the reaction mixture was stirred at room temperature for 1.5 h. After addition of 50 ml of water, it is extracted three times with 30 ml of ethyl acetate each time, the combined organic phases are dried over sodium sulphate and concentrated. Chromatography on 12 g of silica gel [0.046-0.038 mm (230-400 mesh)] using dichloromethane-dichloromethane / methanol 10: 1 gives 80 mg (25%) of the product as a colorless foam.

FAB-MS: 654 (12%, M + H), 533 (100% MC _g H _u N + H).

Example LXVII

6-Ethyl-4-methoxycarbonyl-2-oxo-1- (2 '- (N- (1,1-dimethyl-3-oxo-butyl) tetrazol-5-yl) biphenyl-4-yl) methyl) - 1,2-dihydropyridine

CH ₃

In the preparation of the compound of Example XXXIX, a three-fold amount of 37% hydrochloric acid was used in a variation of the procedure of Example XXXII / A. The title compound is eliminated as a by-product in chromatographic separation.

-41 GB 281937 B6

Yield: 25% as a colorless foam.

1 H-NMR (D ₆ -DMSO): 1.53 (s, 6H), 1.95 (s, 3H), 3.15 (s, 3H).

Example LXVffl

4-Dimethylcarbamoyl-6-ethyl-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

CH ₃

746 mg (1.45 mmol) of the compound of Example LXVII is heated to boiling with 10 ml of methanol and 5 ml of a 40% aqueous dimethylamine solution for 5 minutes. After concentration, the residue is chromatographed on 40 g of silica gel using a 5: 1 mixture of dichloromethane and methanol.

Yield: 73 mg (12%) of a colorless foam.

FAB-MS: 429 (58%; M + H); 154 (100%).

Example LXIX

6-Butyl-4-methoxymethyl-2-oxo-1- (2 '- (N-methyl) -tetrazol-5-yl / biphenyl-4-yl) -methyl) -1,2-dihydropyridine

Analogously to Example XXIX, while stirring for 2 hours at room temperature and for 30 minutes under reflux, from 435 mg (1 mmol) of the compound of Example LV 380 mg (84%) of the product were obtained as a colorless product. foamy substances. This is a 1: 2 mixture of two N-methyl isomers.

-42EN 281937 B6

FAB-MS: 444 (100%, M + H).

1 H-NMR (CDCl 3): 3.23 (s, 2H, N-CH ₃ ); 3.42 (2s, 3H, _OCH3); 4.23 (s, 1H, N-CH _3); 4.3 (s, 2H, CH ₂ -O).

• Example LXX

6-Butyl-4-carboxy-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

4.4 g (10 mmol) of the compound of Example XXXII is stirred in 160 ml of methanol and 7 ml (35 mmol) of 5N sodium hydroxide for 1.5 hours at room temperature. Thereafter, the reaction mixture was treated with 6.5 ml (39 mmol) of 6N hydrochloric acid, concentrated, and the residue was filtered through 200 g of silica gel using dichloromethane / methanol / acetic acid (10: 1: 0.3). An oily residue is obtained from the eluate which is stirred with diethyl ether and filtered off with suction.

Yield: 3.8 g (88%) of a colorless solid.

FAB-MS: 430 (100%, M + H), 452- (30%, M + Na).

Analogously to Example LXX, the compounds listed in Table III are obtained.

Table III COOH 1 N ^ N

Ex. C. R ¹ yield (% of theor.) MS LXXI -nC ₃ H ₇ 84% 417 (100%, M + H) LXXII -C2H5 92% LXXIII - 71% 414 (69%, M + H) LXXIV -n-CjHu 76% ' 445 (70%, M + H)

-43 GB 281937 B6

Example LXXV

6-Butyl-4-methoxycarbonyl-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine potassium salt

1.33 g (3 mmol) of the compound of Example XXXII was dissolved in 30 ml of tetrahydrofuran and 30 ml of methanol, treated with 15 ml of water, and 2.85 ml of 1N sodium hydroxide was added dropwise at about 5 ° C. The reaction mixture is then evaporated to dryness, the residue is stirred in diethyl ether, filtered off and dried in vacuo over phosphorus pentoxide.

Yield: 1.25 g (86.5%) of a colorless amorphous solid.

FAB-MS: 482 (100%, M + H); 520 (20%; M + K).

H-NMR (D ₆₎ DMSO, delta = 0.8 (t, 3H, ZCH, ACHA 3.35 (s, 3H, COOCH, 5.3 (s, 2H, NCHA.

Example LXXVI

6-Butyl-4-isopropyloxycarbonyl-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine sodium

838 mg (1.78 mmol) of the compound of Example XXXVI is dissolved in 5 mL of tetrahydrofuran and 5 mL of water and treated dropwise with 1.69 mL of 1N sodium hydroxide at about 5 ° C. The tetrahydrofuran is then stripped off in vacuo and the residue is lyophilized.

-44GB 281937 B6

Yield: 600 mg (94%) of a colorless foam.

FAB-MS: 516 (100%, M + Na); 494 (70%, M + H).

Analogously to Examples LXXV and LXXVI, the compounds listed in Table IV were prepared.

Table IV

Ex. C. R ^l R ³ R ⁴ M weight '(% theor.) MS according to example no. LXXVII -nC ₄ H ₉ -CO ₂ C ₂ H ₅ H On 96 503 (100%) 480 (96%, M + H) LXXVI LXXVIII -nC ₃ H ₇ - about ₂ ch ₃ H On 88 453 (90%, M + H) LXXVI LXXIX -c, h ₅ - about ₂ ch ₃ H On 94 LXXVI LXXX - about ₂ ch ₃ H On 92 LXXVI LXXXI -nC ₃ H ₇ -COÍW H On*' 98 460 (80%, M + H) 482 (60%, M + Na) LXXV LXXXII -nC ₄ H ₉ -CO ₂ -OCH ₃ H TO 92 467 (100%, M + H) LXXVI LXXXIII -nC ₄ H ₉ -ch ₂ oh H TO 88 455 (10%, M + H) 308 (100%) LXXVI LXXXIV -C2H5 - about ₂ % IP H On*' 98 LXXVI LXXXV -nC ₄ H ₉ -conh ₂ H On 93 LXXVI LXXXVI -nC ₄ H ₉ -CONHCH ₃ H On 98 466 (70%, M + H) 491 (70% M + H) LXXVI LXXXVII -CONH— <] H On 97 469 (100%) Na + H) LXXVI LXXXVIII -nC ₄ H ₉ -ch ₃ H On 98 423 (90%, M + H) 400 (100%, MNa + H) LXXVI LXXXIX > - -CO2P H On*' 98 457 (50%, M + H) 436 (60%, M-Na + H) LXXVI xc -nC ₃ H ₇ - (CH ₂ ) ₂ CH ₃ H On 94 437 (100%, M + H) LXXVI XCI -nC ₄ H ₉ -CON _{(CH3) 2} H On 96 478 (100%, M + H) LXXVI

-45 GB 281937 B6

Example XCII

6-Butyl-4-carboxy-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine disodium salt

A suspension of 0.66 g (1.5 mmol) of the compound of Example XXXII is stirred in 30 ml of tetrahydrofuran and 15 ml of water with 3 ml of 1N sodium hydroxide for 2 hours at room temperature to give a clear solution. It is concentrated to dryness, the residue is stirred in a mixture of tetrahydrofuran and diethyl ether, filtered off with suction and dried over phosphorus pentoxide in vacuo.

Yield: 0.7 g (99%), melting point: from 290 DEG C. (decomposition),

FAB-MS: 474 (70%, M + H); 452 (70%, M-Na + H).

The compounds listed in Table V were prepared analogously to Example XCII. Compounds which could not be obtained by filtration were lyophilized.

Table V

Ex. C. R ¹ R ³ R ⁴ M yield (% of theor.) MS Edukt / př. C. XCIII -nC ₂ H ₅ -cojW CN On 80 XCIV -CcAtP CN On 36 482 (20%, M + H) 461 (100%, M-Na + H) XCV -n-CjH? -cočNtP CN On 99 485 (60%, M + H) XCVI -nC ₄ H ₉ -coíNtP CN On 88 499 (69%, M + H) XCVII CH ₃ OCH ₂ - -coPk? CN TO? 96 518 (50%, M + H) CXLVII XCVIII -n-C.-Hn -COČNíf ⁵ ' H On 99 487 (60%, M + H) XLI XCIX CH ₃ OCH ₂ - -COfNtP H On 100 ALIGN! 463 (40%, M + H) CXLIX

Analogously to Example I / B, the compounds shown in Table VI were prepared using 4'-bromomethyl-triphenyl-2-carboxylic acid tert-butyl ester as the alkylating agent.

-46GB 281937 B6

Table VI

Ex. C. R ³ C -CO ₂ CH, Cl -CO ₂ -CH ₃ -C ₆ H ₅

Example Cil

6-Butyl-4-carboxy-2-oxo-1- [(2'-carboxy-biphenyl-4-yl) methyl] -1,2-dihydropyridine

390 mg (0.71 mmol) of the compound of Example C1 was reacted in 4 mL of dichloromethane with 1 mL of trifluoroacetic acid at 20 ° C. After 3 hours, the reaction mixture was treated with 2M aqueous sodium hydroxide and extracted with diethyl ether. The residual organic solvents were removed in vacuo and the product precipitated from the alkaline solution at 0 ° C with 2M aqueous hydrochloric acid. The precipitate is filtered off with suction, washed with water and dried under high vacuum over phosphorus pentoxide and sodium hydroxide.

Yield: 240 mg (68%).

R _f = 0.09 (dichloromethane-/ methanol = 7: 1).

-47GB 281937 B6

Example Clil

6-Butyl-4-methoxycarbonyl-2-oxo-1 - [(2-carboxy-biphenyl-4-yl) methyl] - (1,2-dihydropyridine)

4.52 g (9.5 mmol) of the compound of Example C was treated in 210 mL of dioxane with 100 mL of 37% hydrochloric acid. After 20 minutes at 20 ° C, it is poured into a mixture of water and ethyl acetate, extracted several times with ethyl acetate, the combined organic phases are dried over anhydrous sodium sulphate and evaporated. Purification by chromatography on silica gel 60 (Meter, from dichloromethane through dichloromethane / methanol 100: 1, 50: 1, 20: 1, 10: 1 to methanol) gave 3.56 g (89%) of the product.

Rf = 0.19 (dichloromethane / methanol 20: 1).

Example CIV

6-Butyl-4-methoxycarbonyl-2-oxo-1- ([2- (4-tolylsulfonylcarbamoyl) biphenyl-4-yl) methyl] -1,2-dihydropyridine

1.063 g (2.53 mmol) of the compound of Example C is reacted in 10 mL of tetrahydrofuran to prevent water at 0 ° C with 0.22 mL (2.78 mmol) of methanesulfonic acid chloride and 0.512 g (5.06 mmol). ) triethylamine. After 30 minutes, 0.52 g (3.04 mmol) of 4-toluenesulfonic acid amide and 0.31 g (2.53 mmol) of 4- (N, N-dimethylamino) pyridine are added and the mixture is heated to 20 ° C. Stir for 20 hours. It is extracted with buffer (pH = 2) and ethyl acetate, the organic phase is dried over sodium sulphate and evaporated. Chromatographic purification (Kiesegel 60, Gauge, dichloromethane-dichloromethane / methanol 100: 1 to 50: 1) afforded 0.83 g (1 mmol) of product.

Rf = 0.50 (dichloromethane / methanol 10: 1).

-48GB 281937 B6

Example CV

6-Butyl-4-methoxymethyl-2-oxo-1 - ([(2'-methylsulfonylcarbamoyl) -biphenyl-4-yl) methyl] -1,2-dihydropyridine

The title compound was prepared in analogy to Example CIV using methanesulfonic acid amide.

Rf = 0.46 (dichloromethane / methanol 10: 1).

Analogously to Example LXX, the compounds shown in Table VII are prepared.

Table VII

Ex. C. R‘S yield (% of theor.) Rf Dichloromethane: MeOH (5: 1) Edukt (ex.) CVI 95 0.17 CIV CVII ch ₃ 71 0.04 CV

-49GB 281937 B6

Example CVIII

6-propyl-3,5-diethoxycarbonyl-2-oxo-l - (/ ^2! - (N-triphenylmethyl-tetrazol-5-yl) -biphenyl-4-yl / methyl) -1,2-dihydropyridine

7.2 g (25.6 mmol) of the compound of Example 23, 0.92 g (30.7 mmol) of sodium hydride (80% in oil) and 14.3 g (25.6 mmol) of N-triphenylmethyl-5- The 2- (4'-bromomethylbiphenyl) tetrazole was stirred overnight in 100 ml of dimethylformamide at 20 ° C. The solvent was then distilled off in vacuo, the residue was dissolved in ethyl acetate, washed with water, dried over anhydrous sodium sulfate and chromatographed on silica gel using petroleum ether / ethyl acetate 10: 1.

Yield: 4.9 g (25% of theory).

Rf = 0.17 (petroleum ether / ethyl acetate 10: 1).

Example CIX

6-Propyl-3,5-bis-ethoxycarbonyl-2-oxo-1- (2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

Analogously to Example XXXII, 1.1 g of the title compound was prepared from 1.9 g (2.5 mmol) of the compound of Example CVIII.

Yield: 85%.

MS (FAB): 516 (M + 1).

-50GB 281937 B6

Example CX

6-Propyl-3-hydroxycarbonyl-5-ethoxycarbonyl-2-oxo-1 - [- 2 &apos; -tetrazol-5-yl-biphenyl-4-yl] -1,2-dihydropyridine

2.0 g (2.6 mmol) of the compound of Example CVIII and 145.6 mg (2.6 mmol) of potassium hydroxide were refluxed in 27 ml of ethanol for 20 minutes. The solvent was then distilled off and the residue was dissolved in water with the addition of 1 g of potassium carbonate. It is washed with ethyl acetate, the aqueous phase is acidified with hydrochloric acid and the precipitated product is crystallized from methylene chloride.

Yield: 0.1 g (5.3% of theory), melting point: 128 DEG C. (decomposition).

Example CXI

6-propyl-2-oxo-l - / (2'-tetrazol-5-yl ^{i-biphenyl-4-yl)} methyl / -l, 2-dihydropyridine-3,5-dicarboxylic acid

1.88 g (2.5 mmol) of the compound of Example CVIII and 1.12 g (20 mmol) of potassium hydroxide were heated under reflux in 50 ml of ethanol for 48 hours. The solvent was distilled off, the residue was dissolved in water, washed with diethyl ether, the aqueous phase was acidified with hydrochloric acid and extracted with ethyl acetate. The organic phase is dried over sodium sulphate, the solvent is distilled off and the residue is triturated with diethyl ether.

Yield: 0.6 g (48% of theory).

SI-MS: 458 (M-H) &lt; - &gt;.

-51 GB 281937 B6

Examples CXII and CXIII

6-Propyl-3-hydroxymethyl-5-ethoxycarbonyl-2-oxo-1- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,2-dihydropyridine

O

(ex CXII)

6-Propyl-3,5-bis (hydroxymethyl) -2-oxo-1- (2 '- (N-triphenylmethyl-tetrazol-5-yl) biphenyl-4-yl) methyl) -1,2-dihydropyridine

(ex CXIII)

0.75 g (0.99 mmol) of the compound of Example CVIII and 0.58 ml (1.98 mmol) of Red-Al (3.4M in toluene) were stirred in 5 ml of tetrahydrofuran for 2 hours at 20 ° C. . The product is hydrolyzed with 25% potassium tartrate solution, washed with ethyl acetate, and the organic phase is washed with saturated sodium chloride solution. It is then dried over anhydrous sodium sulphate and chromatographed on silica gel with a 1: 5 mixture of ethyl acetate and petroleum ether.

Yield: 94 mg (13.5% of theory) (e.g. CXII),

204 mg (29% of theory) (e.g. CXIII).

Rf = 0.35 (ethyl acetate / petroleum ether 1: 1) (e.g. CXII),

R _f = 0.66 (ethyl acetate) (eg. CXIII).

-52EN 281937 B6

Example CXIV

6-Propyl-3-hydroxymethyl-5-ethoxycarbonyl-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

O

Analogously to Example XXXII, 37.6 mg of the title compound is obtained from 85 mg (0.121 mmol) of the compound of Example CXII.

Yield: 66%.

MS (FAB): 474 (M + 1), 496 (M + Na).

Example CXV

6-Propyl-3,5-bis (hydroxymethyl) -2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine

H

Analogously to Example XXXII, 85 mg of the title compound is obtained from 200 g of the compound of Example CXIII.

Yield: 66.3%.

MS (FAB): 432 (M + H), 454 (M + Na).

In analogy to the production methods disclosed herein, the compounds shown in Table VIII are prepared.

-53 GB 281937 B6

Table Vlil

Educt / method according to ex. 125 / CVli | > u CM 128 / IB 1 30 / 1B 1 31 / IB 32 / IB 1 33 / IB 34 / IB 1 X uc cc £ σι ri Cl rr Ό • r m It kO Cl whose Cl rT ri O Cl O O O O O O O O O o ^x O> N> <d 5 00 - rc 'C \O υ-Ί CM \ © Cl > 04 / f * l υ o o o * · X o r-i X u o o - O z Q z u X X O ΰ r * i X o ri o4 </ Ί OF > and o • Λ X sO o X o o o o 0 o o o ω o o 1 ω o o υ 1 ΰ o o u 1 X Q O O O 1 X O o O O X o O o o AND υ m X o γμ Q / o o o o and r O O O O X 1 O 1 r-i X X O 1 fl4 r- 'ί u r * r-o 0 l and" σ * X o 1 r · (J AND O 1 ’Τ o í ru X u o Π) -F · ϋ X o 1 * 1 C·", ΰ 1 U -U O o r * -i O and O <*) O X X o > > »Q> 1J CL. > X u > X Q > X o X X o X X o X X o X X Q X X o X X u

Table Vlil - continued

Educel / method according to ex. C**, 1CXXVI / XXVIII | ICXXV11 / XX1X 1 X X X > X X o CXXVII / Pyridinium chlorochromate Dichloromethane, 39 / IB 1 CXV1I1 / CX1 CXVII / XXVH 1 6-Chloro-pyrid-2-one / 1B | * ✓ * * ··. ΓΊ ΤτΊ ΠΊ un r i o r *. C* C * j O" '/ Ί o' F·*, ΤΓ θ ' Kl Γ- * θ ' 3 u *% yy θ ' 00 O* yield (% of theor.) i / i 3 \ r * 00 r * ’Τ θ 'm O ΓΊ -r and £ ₌ X X X o o o ω X o o o 1 X o ΓΜ X o 1 X r * i aá _{= =} X AND - - r · *, X o CM X o o o o 1 X o r> i X o 1 ₌ Γ4 O CM O o c u 1 '•with at 1 u o r> i O 1 X > o o r-t X o o r-l O 1 o X o 1 X X r- <5 at 1 f * o r · X <* 1 o r » O (· 3 » * r o 1 with* X T o r θ ' T o 1 O > I> J > X X ω > X X o Icxxvm I X X X ω X X X o X X X o X X X ω Icxxxiii I Icxxxiv

Example CXXXV

6-Butyl-1 - [(2 '-tetrazol-5-yl-biphenyl-4-yl) methyl] -pyrid-2-On-3,4-dicarboxylic acid diethyl ester

Analogously to Example XXXII, 0.35 g (51%) of the title compound is obtained from 1 g of the compound of Example CXVIII.

MS (FAB): 530 (M + H), 552 (M + Na).

Example CXXXVI

6-Butyl-1 - [(2 '-tetrazol-5-yl-biphenyl-4-yl) methyl] pyrid-2-one-3,4-dicarboxylic acid

Analogously to Example CXI, 120 mg (0.28 mmol) of Example CXXXV yielded 120 mg of the title compound.

Yield: 88%.

Rf = 0.16 (acetonitrile / water 10: 1).

The compounds listed in Table IX below were prepared, unless otherwise indicated, analogously to Example XXXIIB.

-56GB 281937 B6

Table IX

in.

educt / pr. C. CVIII | | cxin '| c o 1 04 » O 72 X CL O c CO >> 1 co 1 ω 1 X © cxvi | > X o cxix | CXXI cxx | | CXXIl] CXXI11 | CXX1V | cxxv | -and- + - £ <z: X -1- ΓΪ Σ _ '-WITH < 4- Σ Σ Σ Σ £ Σ Σ about what what CO TT E ^x OOO Σ O X © O x © O se O O Ol \O O © O aí x © - Cl O- © x © X θ ' UO Q \ ΙΖΊ rr uo © what Ol Ό UO CO X © About ^- • ^ r *!F heavy theory. Ό 00 O*· 00 © x Ol O © x © x 00 04 / O* 04 / oo 'Yeah ΤΓ 00 O- '>% \ O > X O whose 0) and £ O O G> X 1 1 X z o z o X O at O O X OF O / at and O 1 O at O - X -y. X X T * X X -4- ' SC O X O O O O O ω Ά O O O O O O O O O O O O O O O O O O O and O ω O 1 O O 1 O 1 O 1 O 1 r * j X <* ·> r * l X X 1 ω -AT O O τ ' cm QÍ and' O u o X T · O X ¹ o X - O fM X X X X O O O o o » at 1 -what O O O 1 Γ “» r- 1 -r r-i -O 1 * 1 X X X -r X T -T O O O at and* n-C n-C at 1 C at O O 1 <- O 1 <- O O X- / <- Λ T · ' X τ ' 1 1 > 1 1 at O O > > X X X X - MB > > > > > X xj X X X _4 _J —1 _J _J X X X X X X X X X X X X X and. at O at O O O at O at O O O O

O

-57GB 281937 B6

Table IX - continued

educt / ex. C. > X X υ I cxxvn I | cxxvm I I cxxix I CLIV / method from example CX 1 | cxxx I CXXX1 I CLVIH / method from eg CX 1 CXXX1I I CXXXII / method of Example XXVIII 1 CXXXIV | 04 / 00 qs θ ' m © * O O θ 'o * oc ΓΜ O © CM θ ' yield (% of theor.) r- CM 0 © Gn CJ \ O Γ * - xr o4 - - - - - - <* 5 u r> O u 5 AT' AT q > - 04 / ₌ X X - ₌ - - ₌ r-i at O u 1 rs at 1 ₌ CM 04 / O X o r * ·, O O CM X u <ΖΊ at O O X o and ΰ 1--1 O o o o and o o o 1 O O and - - - - - 04 / X u 1 C X ω 1 C r- X o 1 r * · X u re r * X m u i re 1 ΓX m o 1 C 1 O* X XT u t c and o> X V u 1 C t ku v o r · T o X XT q re 1 O > Q Cl J tj J u u o Yeah > □ at > Yeah > -J u > O > O X Yeah > <J o

O

CQ re 3 C c re re L ·. > 3 □ © O at- “3 >> Ml r ™ re L. w re> re > -x ω O CM O re O YEAH D ⁼ δ O (Λ > o ZC 5Λ re > ‘X ! Z> O 3 at □ -T3 N O L. O JO O <υ N re re O with YEAH '<υ Φ re • * 3 O O r " C/) re C / 5 x O > “» JX >> at 're* O Έ > re O IN) re O rés and) <Zl - · > N X -X O re >> -Ω "re O L ·. > · »> jj u (Λ re> E. ’> X _x o <υ Q re O - * -re re 're * ***} re re_ Ό Her <υ (Λ *re 3 re > * Ξ. '<D 3 re SW Oí Vi Ό oí 3 > O 3. > O _w C C M 0) Έ Ui 0) > » > o -X 3 O O to. C / 5 Cl

distilled off and the remaining aqueous solution was lyophilized.

ífc TE

Table X

educt / ex. E. 1 CXLVl 1 XXXII | xxxn 1 1 nxl Icxlix 1 ΙΙΧΧΧ CLXII | Σ | 464 (60%, M + H) 450 (80%, M + H) 455 (100%, M + Li) | 708 (100%, M + Cs) T Σ / o r- O 00 1,454 (100%, M + H) 482 (40%, M + 1/2 Ca) 930 (30%, 2M + II) 1,452 (100%, M + H) yield (% of theor.) D 00 o r-> Cs Tf O o D O rCs Σ X LZ X X X X X X X Λ Z -j <75 u Λ z Λ OF Λ O ΓΊ «4 OF • T ad XI 0 ' CM O o 1 o u & o o 1 X o CM -r ΰ 1 O CM ΰ 1 X O o O X X CM O CM x ·. O X> w o 1 X X X ₌ X -F· X X X -r X = X X Ií o o 1 X X X X ω CM X o CM O o X o 0 ’O 1 X O 0 'o t X ω CM O O X o CM O o X X o CM O O 1 X X o CM O o 1 ΓΜ XI 0 ' CM O o 1 o u 1 X cm O 0 'o 1 X CM O C | o u 1 CM O ó X X o u CM O CM O ω 1 X X N © u X X CM u CM O u t X ₌ X ru O C-1 o Q o 'o 1 1 CM O CM X u O 1 X ₌ T * X X ~ a £, F CM r-i X o and x X o » CM CM X o x T O > CM C-l F · O 1 x -T * -u> o J CM X o 1 X O 1 CM CM X o 1 ω -r · ' 1 CM CM O 1 o X l-U t CM z — S CM O 1 u X AND CM nO 1 o 1 X X o 1 o X ) X Π * O 1 o 1 X X o ó X X and X C-1 O 1 O CM O 1 o X * T '' M ΰ 1 o C-1 O O X O σ * X o X O X O > U X at X _J o X O > X at > X J o > X J o > X -J > X -J o X X _2 O X X -J u X X O X X at X X —1 O > X X at > X X O > X X _4 O > X X _: Q > X X Yeah

Example CLXXIX

6-Butyl-4-methoxycarbonyl-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine sodium

To a solution of 443 mg (1 mmol) of the compound of Example XXXII in 10 mL of methanol and 5 mL of acetone was added 51 mg (0.95 mmol) of sodium ethyl acetate, then the reaction mixture was concentrated and lyophilized.

Yield: 460 mg (99% of theory) of an amorphous solid.

The compounds listed in Table XI below were prepared according to the recipe therein.

-60GB 281937 B6

Table XI

Ex. C. R ¹⁴ yield (% of theor.) Rf petroleth./ethylac. 1 - 1 1 H-NMR (D ₆ DMSO) (tetrazole-CH-) CLXXX ___N NN \ ch ₃ 40 0.25 4.28 ppm CLXXXI NN NN ch ₃ 44 0.15 3.45 ppm

1.19 g (2.47 mmol) of the compound of Example LXXV was stirred in 30 mL of tetrahydrofuran with 7.770 mg (5.4 mmol) of methyl iodide for 3 days at room temperature. The reaction mixture is then treated with 100 ml of water, extracted three times with 50 ml of dichloromethane each time, and the organic phase is dried, concentrated and chromatographed on 75 g of silica gel using petroleum ether / ethyl acetate (2: 1 - 1: 3). 448 mg (40%) of the compound of Example CLXXXVI and 493 mg (44%) of the compound of Example CLXXVIII are obtained in the form of a colorless amorphous substance.

Starting from the compound of Example CLXIII, the compounds shown in Table XII are prepared.

-61 GB 281937 B6

Table XII

Ex. C. R Rf * in weight reaction conditions CLXXXII CH ₅ CH ₂ O- 0.29 86% 0.5M NaOEt in EtOH, 1 d under reflux. chl. CLXXXIII CH; CH ₂ -S- 0.29 24% 0.16M KSEt in THF 1 d under ref. chl. CLXXXIV ch ₅ ch ₂ -nh. our. H ₂ NEt m. THF, 1 d under rec. chi.

*) mobile phase: dichloromethane / methanol 10: 1

The following compounds, listed in Table XIII, were obtained by Procedure B of Example I.

Table XIII

Ex. C. R ¹ R ² R ^J R ⁴ yield (% of theor.) R _f * starting material (ex.) CLXXXV nC ₄ H ₉ H CN H 28 0.43 40 CLXXXVI nC ₄ H ₉ H NN N - NC (C ₆ H ₅ ) ₃ H 12 0,7 ²⁾ 42 CLXXXVII ch ₃ H COOCH3 H 33 0,27 ²⁾ 6-Methyl-4-methoxycarbonyl-2-oxo-1,2-dihydropyridine CLXXXVIII - (CH ₂ ) ₄ - COOCH3 H 43 0,33 ²⁾ 4-Methoxycarbonyl- 2-oxo-1,2,5,6,7,8- hexahydroquinoline

*) moving petroleum ether / ethyl acetate 9: 1 ²⁾ petroleum ether / ethyl acetate 1: 1.

The compounds listed in Table XIV below are synthesized therein.

-62EN 281937 B6

Table XIV

Method according to example XXXIIB | XXXIIB ¹ ' XXXIIB 1 [XXXIIB | lxx 1 | XCII Base: LiOH | Neutralis. m Cliromatography XCII | Neutralis. m. AcOH Chromatog. LXXVI Base: Agrin. | LXXVI Base: Triethylamine LXXVI Base: Dicthylamine LXXVI Base: NaHCO3 Eastern mater. CLXXXV CLXXVI CLXXXVII [CLXXXVIII I | CLXXXVII 1 | iiiaxxxhdI XCIX CXLIX. CXCVI | iixxxl XXX XXXII CXCVII MS Σ / o ΤΓ O 455 (80%, M + H) 408 (100%, M + H) 442 (100%, M + H) | 387 (80%, M + H) 1425 (40%, M + H) 4.18 (80%, M + 11) 460 (60%, M + H) 417 (100%, M + H) 618 (80%, M + H) 545 (50%, M + 11) 546 (40%, M + H) and 424 (69%, M + H) howl. (%) 00 00 rr Γ * Ί <5 θ ' 1 ⁰⁰¹ 1 © Os Os (N O Os Os o θ ' Os 001 Σ ₌ - - - _1 - 55 OF rN eO u. < 1 z of On = X - - T - - - - -r - - - O: CN T z z II I ZZ r Γ * ·. X o o o u X o o o u δ p u 3_ Ξ ξ 'w / o u COOII ~ C5 Z o COOII X u o o U COOCII1 COOCII, COOCIi, ΓΜ and: = X X - - - - - - ~ aí X O 1 WITH Os X • v u 1 G rn X o 1 CN X u and τ * Ί X o 1 X u 1 CM O ó i X o ΰ CM mL. at X o rq / - “x rn X o o * X rr O 1 C σ » X v o 1 2 X u 1 G • * 1 X o > Oh Mm CU ICLXXXIX CXC Icxci Icxcn I Icxcm | Icxciv I Icxcv Icxcvi CXCVII Icxcvm I cxcix CXC cc

V>

²⁾ H-Arg:

/ - N y COOH h ₂ nh ^ nh ₂ ⁰ twice the conc. HCl

Analogously to Example XCII, the compounds listed in Table XV are synthesized, stirring overnight with one molar equivalent and lyophilized.

Table XV

Ex. C. R ' ⁴ yield (% of theor.) MS starting material CCI N = N - <$ 1 N - N - CH ₃ 97% 467 (70%, M + H) CLXXX CCU _Z N = N - <· 1 N - N 1 CH ₃ 99% 467 (100%, M + H) CLXXXI

Claims (12)

PATENT CLAIMS Substituted biphenylpyridones of general formula I in which (I), R ¹ represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, A represents a direct bond, an oxygen or sulfur atom, or a group -CH ₂ - or a group of formula -NR ⁶ , wherein: R ⁶ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, or R ⁶ together with R ¹ and the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycle, R ² , R ³ and R ⁴ are the same or different and denote a hydrogen atom, a nitro group, a cyano group, a formyl group or a halogen atom or a straight or branched alkyl, alkenyl, alkynyl, alkoxy or alkylthio group of up to 8 carbon atoms; up to twice, equally or differently substituted by hydroxy, cyano, halogen, carboxyl, straight or branched alkoxy, acyl or alkoxycarbonyl of up to 6 carbon atoms, or benzyl, phenyl, phenoxy or benzoyl, or 5- to 7-membered, saturated or an unsaturated heterocycle of up to 3 heteroatoms from the group consisting of oxygen, sulfur and nitrogen, wherein the cycles themselves may be up to twice the same or differently substituted by trifluoromethyl, trifluoromethoxy, halogen, nitro, cyano, hydroxy, hydroxymethyl or propyl; a linear or branched alkyl or alkoxy group having up to 6 carbon atoms in each case; or Straight or branched acyl or alkoxycarbonyl of up to 8 carbon atoms, phenoxycarbonyl, benzyloxycarbonyl or carboxyl, or cycloalkyl or cycloalkenyl of 3 to 8 carbon atoms, 5-membered to 7-membered heterocyclyl sulfur, nitrogen and oxygen, phenyl, phenoxy or phenylthio optionally substituted up to three times the same or differently by halogen, nitro, cyano, hydroxyl, trifluoromethyl, trifluoromethoxy or straight or branched alkyl or alkoxy Or a tetrazolyl group which is optionally substituted by a methyl or tritvl group or a group of the formula HC = N-OH, -C = C CO, R ⁹ -NR ^h R ^I0. -CO-NR ¹⁰ R or -CH ₂ -OR ¹² . whereas R ⁷ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, R ³ denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl or a five-membered to seven-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of sulfur, nitrogen and oxygen, the cyclenes being optionally substituted by hydroxy, hydroxymethyl, halogen or straight or branched alkyl or alkoxy of up to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms, R ⁹ represents a hydrogen atom, a straight or branched alkyl group having up to 8 carbon atoms or a phenyl group, R ¹⁰ and R ¹¹ are the same or different and represent a hydrogen atom, a C 3 -C 8 cycloalkyl group or a straight or branched C 8 -C 8 alkyl group optionally substituted by a phenyl group, R ¹² denotes a straight or branched acyl group having up to 6 carbon atoms or a benzoyl group. or -66GB 281937 B6 -AR and R ² together denote an alkylene chain having up to 5 carbon atoms, R ⁵ represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, D denotes the remainder of the formula R ¹⁴ R ¹³ in which ^Lj R has the abovementioned meaning of R @ ³ and is identical or different and R ¹⁴ represents a group of the formula -CO-R ¹⁵ , -CO-NR ^16, R ¹⁷ or -SO ₂ R ¹⁸ , wherein: R ¹³ denotes hydroxy or a straight or branched alkoxy group having up to 6 carbon atoms, R ¹⁶ and R ¹⁷ are the same or different and have the meanings given above for R ¹⁰ and R ¹¹ , or R ¹⁶ denotes a hydrogen atom and R ¹⁷ denotes the group -SO ₂ R ¹⁸ a R ¹⁸ denotes hydroxyl, straight-chain or branched alkoxy or alkyl each having up to 6 carbon atoms, amino or mono- or dialkylamino each having up to 6 carbon atoms or phenyl group which may be optionally substituted up to twice, identically or differently with halogen, trifluoromethyl or a straight or branched alkyl group having up to 4 carbon atoms, or R ¹⁴ represents a radical of the formula -67EN 281937 B6 in which R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, which is optionally substituted by a straight or branched acyl group of up to 6 carbon atoms, or a triphenylmethyl group, and salts thereof. · Substituted biphenylpyridones according to claim 1 of the general formula I in which R @ ¹ denotes a straight or branched alkyl group of up to 8 carbon atoms optionally substituted by cyclopropyl, cyclopentyl, cyclohexyl, hydroxy or a straight or branched alkoxy group of up to 4 carbon atoms, or cyclopropyl, cyclopentyl, cyclohexyl, atom fluorine, chlorine, bromine or iodine, A represents a direct bond, -CH ₂ , oxygen, sulfur or -NH. R ² , R ³ and R ⁴ are the same or different and denote a hydrogen atom, a nitro group, a cyano group, a formyl group, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom or a straight or branched alkyl, alkenyl, alkynyl or alkylthio group. 6 carbon atoms optionally substituted by hydroxy, cyano, fluorine, chlorine, bromine, carboxyl, straight or branched alkoxy, acyl or alkoxycarbonyl of up to 4 carbon atoms, or benzyl, phenyl, phenoxy, benzoyl or thienyl wherein the cyclenes may themselves be substituted by trifluoromethoxy, trifluoromethyl, hydroxymethyl, fluorine, chlorine, bromine, iodine or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms, or a straight or branched acyl group, or an alkoxycarbonyl group in each case up to 6 carbon atoms, a phenoxycarbonyl group, a benzyloxycarbonyl group or a carboxyl group or a cyclopentenyl, cyclopropyl, cyclopentyl, cyclohexyl, thienyl, furyl, phenyl, phenoxy or phenylthio group optionally substituted up to two times the same or differently with fluorine , iodine, bromine, trifluoromethyl, trifluoromethoxy, hydroxymethyl or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms, or A tetrazolyl group optionally substituted by a methyl or trityl group or a group of the formula R ⁷ I / R ^p -CH = N-OH, -C = C ^X CO ₂ R ⁹ -NR ¹⁰ R, ^{-CO-NR 0} R or -CH ₂ -OR ¹² , wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, R ⁸ denotes a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, which is optionally substituted by cyclopropyl, cyclohexyl, thienyl or phenyl, the cyclenes being optionally substituted by hydroxy, hydroxymethyl or straight or branched alkyl or alkoxy each with up to 4 carbon atoms, R ⁹ denotes a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a cyclopropyl group, a cyclohexyl group or a straight or branched alkyl group having up to 6 carbon atoms which is optionally substituted by a phenyl group, and R ¹² represents a straight or branched acyl group having up to 6 carbon atoms, or -AR ¹ and R ² together represent an alkylene chain of up to 5 carbon atoms, R ⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom, a bromine atom, a hydroxy group, a trifluoromethyl group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 4 carbon atoms each; D denotes the remainder of the formula R ¹⁴ R ¹³ in which -69GB 281937 B6 R ¹³ is as defined above for R ⁵ and is the same or different, and R ¹⁴ represents a group of the formula -CO-R ¹⁵ , -CO-NR ¹⁶ R ¹⁷ or -SO ₂ R ¹⁸ , wherein: R ¹⁵ represents a hydroxy group or a straight or branched alkoxy group having up to 4 carbon atoms, R ¹⁶ and R ¹⁷ are the same or different and have the meanings given above for the substituents R ¹⁰ and R ¹⁶ , or R ^1b denotes a hydrogen atom and R ¹⁷ denotes the group -SO ₂ R ¹⁸ a R ¹⁸ denotes a straight or branched alkyl group having up to 4 carbon atoms or a pentyl group, or R ¹⁴ denotes a radical of formula in which R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, which is optionally substituted by a straight or branched acyl group having up to 4 carbon atoms, or a triphenylmethyl group, and salts thereof. The substituted biphenylpyridones of claim 1, wherein: R @ ¹ denotes a straight or branched alkyl group having up to 6 carbon atoms, which is optionally substituted by a cyclopropyl group, a hydroxy group or a methoxy group, or -70EN 281937 B6 a cyclopropyl group, a chlorine atom or an iodine atom, A denotes a direct bond, -CH ₂ - or an oxygen atom, R ² , R ³ and R ⁴ are the same or different and denote a hydrogen, cyano, formyl, fluorine, chlorine, bromine or iodine atom or a straight or branched alkyl, alkenyl, alkynyl or alkylthio group of up to 4 carbon in each case atoms optionally substituted by hydroxy, cyano or straight or branched alkoxy or alkoxycarbonyl of up to 3 carbon atoms, benzyl, phenyl, phenoxy or benzoyl, or straight or branched acyl or alkoxycarbonyl of up to 4 carbon atoms , a phenoxycarbonyl group, a benzyloxycarbonyl group or a carboxyl group. or a cyclopropyl, cyclopentyl, thienyl, phenyl, phenoxy or phenylthio group optionally substituted by a fluorine atom, a chlorine atom, a bromine atom, an iodine or a trifluoromethyl group, or a tetrazolyl group optionally substituted by a methyl or trityl group, or R ⁷ • I / R ⁸ is -CH = N-OH, -C = C ^X CO ₂ R ⁹ -CO-NR ¹⁰ R or -CH ₂ -OR ¹² , wherein R ⁷ represents a hydrogen atom or a methyl group, ^R denotes hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, which is optionally substituted by phenyl which is itself optionally substituted by hydroxyl, hydroxymethyl or a straight or branched alkyl or alkoxy each having up to 3 carbon atoms. R ⁹ denotes a hydrogen atom or a straight or branched alkyl group of up to 4 carbon atoms, -71 GB 281937 B6 R ¹⁰ and R ¹¹ are the same or different and denote a hydrogen atom, a cyclopropyl group, a cyclopentyl group or a straight or branched alkyl group having up to 4 carbon atoms, which is optionally substituted by a phenyl group, and R ¹² represents a straight or branched acyl group having up to 4 carbon atoms, or -AR ¹ and R ² together denote an alkylene chain of up to 4 carbon atoms, R ⁵ represents a hydrogen atom, a fluorine atom, a chlorine atom or a methyl group; D denotes the remainder of the formula R14 R ¹³ in which R ¹³ denotes a hydrogen atom and R ¹⁴ represents a group of the formula -CO-R ¹⁵ , -CO-NR ¹⁶ R ¹⁷ or -SO ₂ -R ¹⁸ , wherein R ¹³ represents a hydroxy group or a straight or branched alkoxy group having up to 3 carbon atoms. R ¹⁶ and R ¹¹ 'are the same or different and have the meaning given above for the substituents R ¹⁰ and R ¹¹ , or R ¹⁶ denotes a hydrogen atom and R ¹⁷ denotes the group -SO ₂ -R ¹⁸ a R ¹⁸ denotes methyl or p-tolyl, or -72GB 281937 B6 in which R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group having up to 4 carbon atoms, which is optionally substituted by a straight or branched acyl group having up to 4 carbon atoms, or a triphenylmethyl group, and salts thereof. The substituted biphenylpyridones of claim 1 for therapeutic application. A process for the preparation of substituted biphenylpyridones according to claim 1 of the general formula I (I). in which R ¹ represents straight-chain or branched alkyl having up to 10 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, hydroxyl or by straight-chain or branched alkoxy having up to 6 carbon atoms or cycloalkyl having 3 to 6 carbon atoms, A represents a direct bond, an oxygen or sulfur atom, or a group -CH ₂ - or a group of formula -NR ⁶ , wherein: R ⁶ represents a hydrogen atom or a straight or branched alkyl group of up to 6 carbon atoms, or R ⁶ together with R ¹ and the nitrogen atom to which they are attached form a 5- or 6-membered saturated or unsaturated heterocycle, R ² , R ³ and R ⁴ are the same or different and denote a hydrogen atom, a nitro group, a cyano group, a formyl group or a halogen atom or a straight or branched alkyl, alkenyl, alkynyl, alkoxy or alkylthio group of up to 8 carbon atoms; up to two times, equally or differently substituted by hydroxy, cyano, halogen, carboxyl A straight-chain or branched alkoxy, acyl or alkoxycarbonyl group having up to 6 carbon atoms each, or a benzyl, phenyl, phenoxy or benzoyl group, or a 5- to 7-membered, saturated or unsaturated heterocycle of up to 3 heteroatoms from the group comprising oxygen , sulfur and nitrogen, wherein the cycles themselves may be up to twice the same or differently substituted with trifluoromethyl, trifluoromethoxy, halogen, nitro, cyano, hydroxy, hydroxymethyl or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms, or straight or a branched acyl or alkoxycarbonyl group of up to 8 carbon atoms each, a phenoxycarbonyl group, a benzyloxycarbonyl group or a carboxyl group, or a cycloalkyl or cycloalkenyl group of 3 to 8 carbon atoms each, of five to seven a membered unsaturated heterocycle with up to 3 heteroatoms selected from the group consisting of sulfur, nitrogen and oxygen, phenyl, phenoxy or phenylthio optionally substituted up to three times the same or differently with halogen, nitro, cyano, hydroxyl, trifluoromethyl or trifluoromethoxy or a branched alkyl or alkoxy group in each case having up to 6 carbon atoms, or a tetrazolyl group optionally substituted by a methyl or trityl group, or a group of the formula R ⁷ II / R ³ HC = N-OH, -C = C ^x CO ₂ R ⁹ -NR ¹⁰ R, -CO-NR ¹¹ or -CH ₂ -OR ¹² , wherein R ⁷ represents a hydrogen atom or a straight or branched alkyl group having up to 6 carbon atoms, ^R denotes hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl or a five-membered to seven-membered saturated or unsaturated heterocycle having up to 3 heteroatoms from the group consisting of sulfur, nitrogen and oxygen, the cyclenes being optionally substituted by hydroxy, hydroxymethyl, halogen or straight or branched alkyl or alkoxy of up to 6 carbon atoms, or cycloalkyl of 3 to 6 carbon atoms, R ⁹ represents a hydrogen atom, a straight or branched alkyl group of up to 8 carbon atoms or a phenyl group. R ¹⁰ and R ¹⁰ are the same or different and represent a hydrogen atom, a C 3 -C 8 cycloalkyl group or a straight or branched alkyl group of up to 8 carbon atoms optionally substituted by a phenyl group, and -74EN 281937 B6 R ¹² represents a straight or branched acyl group having up to 6 carbon atoms or a benzoyl group, or -AR ¹ and R ² together denote an alkylene chain of up to 5 carbon atoms, R ⁵ represents a hydrogen atom, a halogen atom, a cyano group, a nitro group, a trifluoromethyl group, a hydroxy group, a trifluoromethoxy group or a straight or branched alkyl or alkoxy group of up to 6 carbon atoms each, and D denotes the remainder of the formula R ¹⁴ R ¹³ in which R ¹³ is as defined above for R ³ and is the same or different thereto, and R ¹⁴ represents a group of the formula -CO-R ¹⁵ , -CO-NR ¹⁶ R ¹⁷ or -SO ₂ R ¹⁸ , wherein R ¹³ denotes hydroxy or a straight or branched alkoxy group having up to 6 carbon atoms, R ¹⁶ and R ¹⁷ are identical or different and have the abovementioned meaning of R ¹⁰ and R ^u or R ¹⁶ denotes a hydrogen atom and R ¹⁷ denotes the group -SO ₂ R ¹⁸ a R ¹⁸ denotes a hydroxy group, a straight or branched alkoxy or alkyl group having up to 6 carbon atoms each, an amino group or a mono- or dialkylamino group having up to 6 carbon atoms each, or a phenyl group which may be optionally substituted up to twice, identical or differently with halogen, a trifluoromethyl group or a straight or branched alkyl group having up to 4 carbon atoms, or R ¹⁴ represents a radical of the formula -75GB 281937 B6 I Ψ I Ν-γ — ν R ¹⁹ in which R ¹⁹ represents a hydrogen atom or a straight or branched alkyl group of up to 8 carbon atoms, which is optionally substituted by a straight or branched acyl group of up to 6 carbon atoms, or a triphenylmethyl group. and their salts, characterized in that pyridones of the general formula II in which R ^1, R ^2, R ⁴ and A have the abovementioned meaning, are reacted with compounds of formula III L (ΠΙ) in which E represents a halogen atom, preferably bromine, and L represents a radical of formula _R 20 -76GB 281937 B6 in which R ¹³ is as defined above, and 5 R ²⁰ denotes a C 1 -C 4 alkoxycarbonyl group or a radical of the formula -O * C (C ₆ H ₅ ) ₃ N-N in inert solvents, in the presence of a base and optionally with the addition of a catalyst, and then in the case of a tetrazole rest of the triphenylmethyl group is removed with acids in organic solvents and / or water, and optionally the thus obtained compound of formula I, R ^2, R ^3, R ^4, R \ R ^13, R ^14, R ¹⁹ and R ° derivatized and / or mutually vary to the extent defined in claim 1. The process according to claim 5, wherein the reaction is carried out at a temperature in the range of -100 ° C to 100 ° C. Pharmaceutical composition for the treatment of hypertension and atherosclerosis, characterized in that it contains at least one substituted biphenylpyridone of the formula I as claimed in claims 1 to 3. Substituted biphenylpyridones of the general formula I according to claim 1 for the manufacture of medicaments. Substituted biphenylpyridones of the general formula I according to claim 1 for the manufacture of medicaments for the treatment of high blood pressure and atherosclerosis. 10. A compound according to claim 1 which is 6-butyl-4-ethoxycarbonyl-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine and salts thereof. 6. A compound according to claim 1 which is 6-butyl-440 methoxycarbonyl-2-oxo-1 - [(2 &apos; -tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2- dihydropyridine and its salts. 12. A compound according to claim 1 which is 6-butyl-4-carboxy-2-oxo-1 - [(2'-tetrazol-5-yl-biphenyl-4-yl) methyl] -1,2-dihydropyridine and salts thereof.